The Journal of Neuroscience , August 1 , 2007 27 -LRB- 31 -RRB- : 8161 8165 8161 Mini-Review The Role of the Dorsal Striatum in Reward and Decision-Making Bernard W. Balleine ,1 Mauricio R. Delgado ,2 and Okihide Hikosaka3 Department of Psychology and the Brain Research Institute , University of California Los Angeles , Los Angeles , California 90095-1563 , 2Department of Psychology , Rutgers University , Newark , New Jersey 07102 , and 3Laboratory of Sensorimotor Research , National Eye Institute , National Institutes of Health , Bethesda , Maryland 20892-4435 1 Although the involvement in the striatum in the refinement and control of motor movement has long been recognized , recent description of discrete frontal corticobasal ganglia networks in a range of species has focused attention on the role particularly of the dorsal striatum in executive functions . Current evidence suggests that the dorsal striatum contributes directly to decision-making , especially to action selection and initiation , through the integration of sensorimotor , cognitive , and motivational/emotional information within specific corticostriatal circuits involving discrete regions of striatum . We review key evidence from recent studies in rodent , nonhuman primate , and human subjects . Key words : choice ; utility ; frontal cortex ; executive ; reward ; striatum To choose appropriately between distinct courses of action requires the ability to integrate an estimate of the causal relationship between an action and its consequences , or outcome , with the value , or utility , of the outcome . Any attempt to base decision-making solely on cognition fails fully to determine action selection because any information , such as `` action A leads to outcome O , '' can be used both to perform A and to avoid performing A . It is interesting to note in this context that , although there is an extensive literature linking the cognitive control of executive functions specifically to the prefrontal cortex -LRB- Goldman-Rakic , 1995 ; Fuster , 2000 -RRB- , more recent studies suggest that these functions depend on reward-related circuitry linking prefrontal , premotor , and sensorimotor cortices with the striatum -LRB- Chang et al. , 2002 ; Lauwereyns et al. , 2002 ; Tanaka et al. , 2006 -RRB- . Importantly , evidence from a range of species suggests that this corticostriatal network controls functionally heterogeneous decision processes involving -LRB- 1 -RRB- actions that are more flexible or goal directed , sensitive to rewarding feedback , and mediated by discrete regions of association cortices particularly medial , orbitomedial , premotor , and anterior cingulate cortices together with their targets in caudate/dorsomedial striatum -LRB- Haruno and Kawato , 2006 ; Levy and Dubois , 2006 -RRB- ; and -LRB- 2 -RRB- actions that are stimulus bound , relatively automatic or habitual , and mediated by sensorimotor cortices and dorsolateral striatum/putamen -LRB- Jog et al. , 1999 ; Poldrack et al. , 2001 -RRB- . These processes have been argued to depend on distinct learning rules -LRB- Dickinson , 1994 -RRB- Received April 6 , 2007 ; revised June 4 , 2007 ; accepted June 4 , 2007 . This work was supported by National Institute of Mental Health Grant 56446 -LRB- B.W.B. -RRB- and by the National Eye Institute Intramural Research Program -LRB- O.H. -RRB- . Correspondence should be addressed to Bernard W. Balleine , Department of Psychology , Box 951563 , Los Angeles , CA 90095-1563 . E-mail : balleine@psych.ucla.edu . DOI : 10.1523 / JNEUROSCI.1554-07.2007 Copyright 2007SocietyforNeuroscience 0270-6474/07 / 278161-05 $ 15.00 / 0 and , correspondingly , distinct forms of plasticity -LRB- Partridge et al. , 2000 ; Smith et al. , 2001 -RRB- . Furthermore , degeneration in these corticostriatal circuits has been linked to distinct forms of psychopathology , e.g. , in Huntington 's , obsessive compulsive disorder , and Tourette 's syndrome on the one hand -LRB- Robinson et al. , 1995 ; Bloch et al. , 2005 ; Hodges et al. , 2006 -RRB- and in Parkinson 's and multiple system atrophy on the other -LRB- Antonini et al. , 2001 ; Seppi et al. , 2006 -RRB- . Here , we review recent evidence implicating the dorsal striatum in decision-making and point to the considerable commonalities in the functionality of this region in rodent , nonhuman primate , and human subjects . Instrumental conditioning in rats Behavioral research over the last two decades has identified forms of learning in rodents homologous to goal-directed and habitual learning in humans . This suggestion is based on extensive evidence that choice between different actions , e.g. , pressing a lever or pulling a chain when these actions earn different food rewards , is determined by the animals ' encoding the association between a specific action and outcome and the current value of the outcome ; choice is sensitive both to degradation of the action outcome contingency and to outcome revaluation treatments -LRB- Dickinson and Balleine , 1994 ; Balleine and Dickinson , 1998 -RRB- . In contrast , when actions are overtrained , decision processes become more rigid or habitual ; performance is no longer sensitive to degradation and devaluation treatments but rather is controlled by a process of sensorimotor association -LRB- Dickinson , 1994 ; Dayan and Balleine , 2002 -RRB- . As such , whereas action outcome encoding appears to be mediated by a form of errorcorrection learning rule , the development of habits is not -LRB- Dickinson , 1994 -RRB- ; indeed , traditionally this form of learning has been argued to be sensitive to contiguity rather than contingency -LRB- Dickinson et al. , 1995 -RRB- . 8162 J. Neurosci. , August 1 , 2007 27 -LRB- 31 -RRB- : 8161 8165 Balleine et al. Dorsal Striatum in Reward and Decision-Making Recent experiments have started to reveal differences in the circuitry associated with these distinct forms of decision process in rodents -LRB- see Fig. 1 -RRB- . Cell body lesions of prefrontal cortex , particularly the dorsal prelimbic -LRB- Balleine and Dickinson , 1998 ; Corbit and Balleine , 2003 -RRB- , but not infralimbic -LRB- Killcross and Coutureau , 2003 -RRB- , region abolishes the acquisition of goal-directed actions , and performance is acquired by sensorimotor association alone . Prelimbic involvement in goaldirected learning is , however , limited to acquisition -LRB- Ostlund and Balleine , 2005 ; Hernandez et al. , 2006 -RRB- , suggesting that this cortical region is involved in learningrelated plasticity localized to an efferent structure . Prelimbic cortex projects densely to both dorsomedial striatum and accumbens core -LRB- Gabbott et al. , 2005 -RRB- and , although well controlled studies assessing specifically goal-directed learning suggests that the latter region is not involved in this learning process -LRB- Corbit et al. , 2001 -RRB- , recent evidence has implicated dorsomedial striatum -LRB- Balleine , 2005 -RRB- . Thus , both pretraining and posttraining lesions -LRB- Yin et al. , 2005c -RRB- , muscimol-induced inactivation -LRB- Yin et al. , 2005c -RRB- , and the infusion of the NMDA-antagonist AP5 -LRB- Yin et al. , 2005b -RRB- within a posterior region of dorsomedial striatum all abolish goal-directed learning and render choice performance insensitive to both contingency degradation and outcome devaluation treatments , i.e. , choice Figure 1 . Corticostriatal circuits involved in decision-making . a , b , The learning processes controlling the acquisition of becomes rigid and habitual -LRB- Yin et al. , reward-related actions are mediated by converging projections from regions of anteromedial prefrontal cortex -LRB- MPC -RRB- to the 2005a -RRB- . rodent dorsomedial striatum or primate dorsoanterior striatum -LRB- DM -RRB- , whereas the processes mediating the acquisition of Interestingly , evidence suggests that a stimulus-bound actions , or habits , are thought to be mediated by projections from sensorimotor cortex -LRB- SM -RRB- to the rodent parallel corticostriatal circuit involving in - dorsolateral primate dorsoposterior striatum -LRB- DL -RRB- -LRB- b -RRB- . These corticostriatal connections are parts of distinct feedback loops that fralimbic and sensorimotor cortices to - project back to their cortical origins via substantia nigra pars reticulata -LRB- SNr -RRB- / globus pallidus internal segment -LRB- GPi -RRB- and the gether with the dorsolateral striatum in ro - mediodorsal -LRB- MD -RRB- / posterior -LRB- PO -RRB- nuclei of the thalamus . c , Reward and predictors of reward are the major motivational infludents may mediate the transition to ences on the performance of goal-directed and habitual actions that are thought to be mediated by corticostriatal circuits habitual decision processes associated with involving , particularly , ventral striatum -LRB- VS -RRB- and regions of the amygdala . Dopamine is an important modulator of plasticity in the sensorimotor learning -LRB- Jog et al. , 1999 ; dorsal striatum , whereas its tonic release has long been associated with the motivational processes mediated by the ventral Killcross and Coutureau , 2003 ; Barnes et circuit . VTA , Ventral tegmental area ; SNc , substantia nigra pars compacta . al. , 2005 -RRB- . Whereas the infralimbic region more medial corticostriatal circuit consistent with the general has been argued to mediate aspects of the reinforcement signal claim that distinct corticostriatal networks control different controlling sensorimotor association -LRB- Balleine and Killcross , forms of decision process -LRB- Daw et al. , 2005 -RRB- . 2006 -RRB- , changes in motor and dorsolateral striatum appear to be training related -LRB- Costa et al. , 2004 ; Hernandez et al. , 2006 ; Tang et Striatal-based learning processes in nonhuman primates al. , 2007 -RRB- and to be coupled to changes in plasticity as behavioral Similarly , recent studies using nonhuman primates have sugprocesses become less flexible -LRB- Costa et al. , 2006 ; Tang et al. , gested that the striatum may be an important brain area in 2007 -RRB- . Correspondingly , whereas overtraining causes perfordecision-making . A clue to this hypothesis came from single-unit mance to become insensitive to outcome devaluation , lesions of recording studies using trained animals . Neurons responding to dorsolateral striatum reverse this effect rendering performance task-related sensory events that become active before task-related goal-directed and once again sensitive to outcome devaluation motor behaviors and that are tonically active until expected retreatments -LRB- Yin et al. , 2004 -RRB- . Likewise , muscimol inactivation of wards are delivered have been described in a circumscribed redorsolateral striatum renders otherwise habitual performance gion of dorsal striatum -LRB- Hikosaka et al. , 1989 ; Hollerman et al. , sensitive to changes in the action outcome contingency -LRB- Yin et 1998 -RRB- . Importantly , the activity of these neurons has been found al. , 2005a -RRB- . Current evidence suggests , therefore , that , whereas to be modulated by the expected presence , amount , or probabilstimulus-mediated action selection is mediated by this lateral ity of reward or by the magnitude of attention or memory recorticostriatal circuit , the more flexible , outcome-mediated acquired to execute the task -LRB- Kawagoe et al. , 1998 ; Shidara et al. , tion selection subserving goal-directed action is mediated by a Balleine et al. Dorsal Striatum in Reward and Decision-Making J. Neurosci. , August 1 , 2007 27 -LRB- 31 -RRB- : 8161 8165 8163 1998 ; Cromwell and Schultz , 2003 -RRB- . The coexpression of the sensorimotor , cognitive , and motivational/emotional signals in single neurons provides conditions favorable for learning . Some of the recent studies addressed this question more directly by examining neuronal activity while the animals were learning new sensorimotor associations , new motor sequences , or adapting to new reward outcomes . They found that , indeed , many striatal neurons decrease or increase their activity as learning progressed -LRB- Tremblay et al. , 1998 ; Blazquez et al. , 2002 ; Miyachi et al. , 2002 ; Hadj-Bouziane and Boussaoud , 2003 ; Brasted and Wise , 2004 -RRB- . Notably , visuomotor -LRB- saccadic -RRB- activity appropriate for the correct saccadic response appeared earlier in the associative striatum -LRB- caudate nucleus -RRB- than in the dorsolateral prefrontal cortex during the course of learning -LRB- Pasupathy and Miller , 2005 -RRB- . The results of single-unit recordings were further supported by experimentally manipulating learning-related neuronal activity . An orthodox method was to suppress activity of neurons in a small functional area in the striatum by injecting GABA agonists such as muscimol . Consistent with dissociations observed in rodents , the suppression of the anterior , associative striatum disrupted learning of new sequential motor procedures , whereas the suppression of the putamen disrupted execution of well learned motor sequences -LRB- Miyachi et al. , 1997 -RRB- . A second method has sought to promote learning by electrically stimulating the striatum -LRB- Nakamura and Hikosaka , 2006b ; Williams and Eskandar , 2006 -RRB- . Importantly , this was effective only when the stimulation was applied just after the animal executed a motor response correctly . The timing specificity raises the possibility that sensorimotor , cognitive , and motivational/emotional signals reach single striatal neurons concurrently at the time around the motor execution to cause plastic changes in synaptic mechanisms . These experiments on learning have been conducted mostly in the dorsal striatum in which motivational/emotional signals from cortex are thought to be sparse . Rather , it appears more likely that motivational signals are supplied by dopaminergic inputs originating mainly from the substantia nigra pars compacta . It has been hypothesized that dopaminergic neurons encode a mismatch between the expected and the actual reward value -LRB- Schultz , 1998 -RRB- . This so-called reward prediction error signal is ideal for guiding learning until the gain of reward is maximized -LRB- Houk et al. , 1995 -RRB- . Indeed , studies on the synaptic mechanisms in the striatum have shown that long-term potentiation -LRB- LTP -RRB- or long-term depression -LRB- LTD -RRB- can occur in the corticostriatal synapses depending on the combination of cortical inputs , striatal outputs , and D1 and D2 dopaminergic inputs -LRB- Reynolds and Wickens , 2002 -RRB- . A study using behaving animals showed that these mechanisms are necessary for behavioral adaptation of motor behavior to changing reward-position contingencies -LRB- Nakamura and Hikosaka , 2006a -RRB- . Local injections of a D1 antagonist into the caudate nucleus lengthened the motor -LRB- saccadic -RRB- reaction times when large rewards were expected , whereas injections of a D2 antagonist lengthened the reaction times when small rewards were expected . Action contingency learning in the human dorsal striatum Studies in humans corroborate the research in animals suggesting that the dorsal striatum is an integral part of a circuit involved in decision-making . Accumulating evidence , primarily from neuroimaging but also neuropsychological investigations , has implicated the dorsal striatum in different aspects of motivational and learning processes that support goal-directed action . For instance , positron emission tomography -LRB- PET -RRB- studies report in - creases in dopamine release in the dorsal striatum -LRB- as measured by displacement of endogenous dopamine by radioligands -RRB- when participants are presented with potential rewards , such as the opportunity to gain money -LRB- Koepp et al. , 1998 ; Zald et al. , 2004 -RRB- or even when presented with food stimuli while in a state of hunger -LRB- Volkow et al. , 2002 -RRB- . Similarly , fMRI studies typically report increases in blood oxygenation level dependent -LRB- BOLD -RRB- responses in the dorsal striatum during anticipation of either primary -LRB- O'Doherty et al. , 2002 -RRB- or secondary -LRB- Knutson et al. , 2001 -RRB- rewards , much like the ventral striatum . What distinguishes the human dorsal striatum from the rest of the basal ganglia is its involvement in action-contingent learning -LRB- Delgado et al. , 2000 , 2005a ; Knutson et al. , 2001 ; Haruno et al. , 2004 ; O'Doherty , 2004 ; Tricomi et al. , 2004 -RRB- . Similar to the animal literature -LRB- Ito et al. , 2002 ; Yin et al. , 2005c -RRB- , learning about actions and their reward consequences involves the dorsal striatum -LRB- O'Doherty et al. , 2004 ; Tricomi et al. , 2004 -RRB- , as opposed to more passive forms of appetitive learning found to depend on the ventral striatum -LRB- O'Doherty , 2004 -RRB- . These results mirror neuropsychological studies conducted on patients afflicted with Parkinson 's disease , who are impaired in their learning of probabilistic stimuli when action contingencies are present -LRB- Poldrack et al. , 2001 -RRB- but are unimpaired when no contingency between action and outcome exists -LRB- Shohamy et al. , 2004 -RRB- . Within the human dorsal striatum , learning of action reward associations has been found in both putamen and caudate nucleus with potentially different roles based on their sensorimotor or associative connectivity , respectively -LRB- Alexander and Crutcher , 1990 -RRB- . Some studies argue , for example , that the putamen is important for stimulus action coding -LRB- Haruno and Kawato , 2006 -RRB- . In contrast , a number of studies suggest that the head of the caudate nucleus is involved in coding reward-prediction errors during goaldirected behavior -LRB- Davidson et al. , 2004 ; O'Doherty et al. , 2004 ; Delgado et al. , 2005a ; Haruno and Kawato , 2006 -RRB- . More recently , neuroimaging studies have extended these general ideas on the function of the human dorsal striatum to more complex social issues . Increases in BOLD responses in the dorsal striatum , for example , have been reported when an interactive social component exists , such as the occurrence of cooperation -LRB- Rilling et al. , 2002 -RRB- or revenge -LRB- de Quervain et al. , 2004 -RRB- . The caudate nucleus has also been implicated in the acquisition of social reputations -LRB- via reciprocity in an economic exchange game , the `` trust game '' -RRB- through trial and error -LRB- King-Casas et al. , 2005 -RRB- . However , existing social biases -LRB- e.g. , knowledge about moral characteristics -RRB- can also hinder corticostriatal learning mechanisms and influence subsequent decisions -LRB- Delgado et al. , 2005b -RRB- . A future challenge for researchers is , therefore , to understand the role of the dorsal striatum in goal-directed behaviors with respect to the vast array of existing social complexities . Summary and future directions Together , this recent evidence suggests that the dorsal striatum mediates important aspects of decision-making , particularly those related to encoding specific action outcome associations in goal-directed action and the selection of actions on the basis of their currently expected reward value . We have summarized these findings and the major trends in research that they imply in Figure 1 . These findings are consistent with computational theories of adaptive behavior , notably forms of reinforcement learning , and when considered in the context of current views of the broader corticobasal ganglia system , appear likely to provide the basis for an integrated approach to striatal function . Important questions still remain , such as the anatomical and 8164 J. Neurosci. , August 1 , 2007 27 -LRB- 31 -RRB- : 8161 8165 Balleine et al. 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O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B I O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O B O O O O O O O

striatum
review
basal ganglia
decision
dopamine
reward
reinforcement learning


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transgenic

mice

P.

Glazer

for

mice

S.

Fugmann

M.

Shlomchik

and

M.

Diaz

for

critical

reading

of

the

manuscript

G.

Tokmoulina

for

help

with

cell

sorting

the

Yale

Transgenic

Mouse

Service

for

generating

transgenic

mice

the

Keck

Facility

at

Yale

Medical

School

and

the

Broad

Institute

for

DNA

sequencing

and

the

members

of

the

Schatz

lab

for

stimulating

discussions

S.U.

is

a

postdoctoral

associate

and

D.G.S.

is

an

investigator

of

the

Howard

Hughes

Medical

Institute

Figs

to

Tables

and

References

Supporting

Online

Material

Materials

and

Methods

May

accepted

July

science

Localization

of

a

Stable

Neural

Correlate

of

Associative

Memory

Leon

G.

Reijmers

Brian

L.

Perkins

Naoki

Matsuo

Mark

Mayford

Do

learning

and

retrieval

of

a

memory

activate

the

same

neurons

Does

the

number

of

reactivated

neurons

correlate

with

memory

strength

We

developed

a

transgenic

mouse

that

enables

the

long-lasting

genetic

tagging

of

c-fos

active

neurons

We

found

neurons

in

the

basolateral

amygdala

that

are

activated

during

Pavlovian

fear

conditioning

and

are

reactivated

during

memory

retrieval

The

number

of

reactivated

neurons

correlated

positively

with

the

behavioral

expression

of

the

fear

memory

indicating

a

stable

neural

correlate

of

associative

memory

The

ability

to

manipulate

these

neurons

genetically

should

allow

a

more

precise

dissection

of

the

molecular

mechanisms

of

memory

encoding

within

a

distributed

neuronal

network

M

emories

are

presumably

stored

in

subgroups

of

neurons

that

are

activated

in

response

to

a

given

conjunction

of

sensory

inputs

Sparse

encoding

of

memories

in

complex

neuronal

networks

has

been

identified

with

electrophysiological

recordings

of

large

groups

of

single

units

-LRB-

-RRB-

Similar

approaches

Department

of

Cell

Biology

The

Scripps

Research

Institute

La

Jolla

CA

USA

To

whom

correspondence

should

be

addressed

E-mail

mmayford@scripps.edu

have

identified

neurons

with

firing

properties

temporally

linked

to

various

aspects

of

task

performance

-LRB-

-RRB-

and

imaging

techniques

have

enabled

the

physical

localization

of

neurons

that

are

activated

during

either

learning

or

retrieval

of

a

memory

-LRB-

-RRB-

In

an

associative

task

the

sensory

stimuli

and

their

temporal

relationships

differ

during

the

learning

and

retrieval

trial

and

it

is

unclear

to

what

extent

the

neuronal

representations

of

these

two

events

overlap

We

generated

a

transgenic

mouse

-LRB-

TetTag

mouse

-RRB-

that

allows

the

persistent

tagging

of

A

Fos-prom

tTA

doxycycline

tTA

TetO

tauLacZ

tTA

TetO

tauLacZ

Fos-prom

tTA

Fos-prom

tTA

doxycycline

tTA

TetO

tauLacZ

B

mouse

mouse

mouse

mouse

neuron

A

neuron

B

neuron

C

doxycycline

no

doxycycline

doxycycline

seizure

doxycycline

home

cage

seizure

days

later

doxycycline

Fig.

-LRB-

A

-RRB-

Tagging

of

activated

neurons

is

achieved

by

two

transgenes

present

in

the

TetTag

mouse

TetTag

mice

are

raised

on

food

containing

Dox

-LRB-

left

yellow

block

-RRB-

During

this

time

neuronal

activation

-LRB-

indicated

by

lightning-bolt

symbols

-RRB-

that

leads

to

expression

of

tTA

through

c-fos

promoter

activation

will

not

trigger

tagging

because

Dox

blocks

activation

-LRB-

indicated

by

the

red

x

-RRB-

of

the

tetO

promoter

-LRB-

see

neuron

A

-RRB-

The

time

window

for

tagging

is

opened

by

switching

mice

to

food

without

Dox

-LRB-

middle

white

block

-RRB-

Neuronal

activation

will

now

activate

the

transcriptional

feedback

loop

and

start

expression

of

tau-LacZ

-LRB-

see

neuron

B

-RRB-

The

time

window

is

closed

by

putting

mice

back

on

Dox

food

-LRB-

right

yellow

block

-RRB-

to

block

further

feedback

loop

activation

-LRB-

see

neuron

C

-RRB-

However

neurons

that

were

activated

during

the

no

Dox

time

window

will

continue

to

express

tau-LacZ

-LRB-

see

neuron

B

-RRB-

because

the

feedback

loop

can

maintain

its

own

activation

through

the

Dox-insensitive

-LRB-

tTA

-RRB-

where

represents

-LRB-

B

-RRB-

Kainic

acid

induced

seizures

were

used

to

test

whether

Dox

can

be

used

to

open

a

time

window

for

tagging

activated

neurons

In

the

presence

of

Dox

no

neurons

are

tagged

after

induction

of

seizure

as

indicated

by

X-Gal

-LRB-

5-bromo4-chloro-3-indolyl-b-D-galactopyranoside

-RRB-

staining

of

a

coronal

section

-LRB-

mouse

-RRB-

When

a

TetTag

mouse

is

left

in

the

home

cage

in

the

absence

of

Dox

only

a

limited

number

of

neurons

are

tagged

-LRB-

mouse

-RRB-

Seizure

in

the

absence

of

Dox

triggers

the

tagging

of

a

large

number

of

neurons

throughout

the

forebrain

as

can

be

seen

at

hours

-LRB-

mouse

-RRB-

and

days

-LRB-

mouse

-RRB-

after

seizure

Mouse

was

put

on

Dox

food

immediately

after

seizure

time

window

for

tagging

activated

neurons

AUGUST

VOL

SCIENCE

Downloaded

from

on

May

neurons

that

are

activated

during

a

given

time

window

-LRB-

Fig.

-RRB-

The

tag

can

be

used

for

the

direct

comparison

of

neuronal

ensemble

activity

at

two

widely

spaced

time

points

The

TetTag

mouse

combines

elements

of

the

tetracyclinetransactivator

-LRB-

tTA

-RRB-

system

for

transgene

regulation

with

neuronal

activity

induced

activation

of

the

c-fos

promoter

to

tag

activated

neurons

-LRB-

-RRB-

We

used

seizure-induced

neuronal

activation

to

test

various

aspects

of

regulation

in

the

TetTag

mouse

As

shown

in

Fig.

tauLacZ

-LRB-

LAC

-RRB-

expression

had

a

low

baseline

could

be

induced

broadly

in

the

brain

by

seizure

in

a

doxycycline

-LRB-

Dox

-RRB-

regulated

manner

-LRB-

figs

and

-RRB-

and

could

be

maintained

for

at

least

days

in

the

presence

of

Dox

after

the

initial

activation

The

TetTag

mouse

was

used

to

determine

whether

neurons

that

are

activated

during

learning

are

reactivated

during

retrieval

We

used

expression

of

LAC

as

an

indicator

of

neuronal

activity

during

learning

and

expression

of

the

immediate-early

gene

Zif/Egr

-LRB-

ZIF

-RRB-

as

an

indicator

of

neuronal

activity

during

retrieval

-LRB-

Fig.

-RRB-

-LRB-

-RRB-

We

assessed

associative

memory

using

fear

conditioning

with

a

focus

on

the

learning

and

retrieval

of

a

context-shock

association

-LRB-

-RRB-

The

basolateral

amygdala

-LRB-

BLA

-RRB-

has

been

implicated

as

a

potential

storage

site

for

context-shock

associations

-LRB-

-RRB-

Using

the

REPORTS

TetTag

mice

we

were

able

to

identify

neurons

in

the

BLA

that

express

both

LAC

and

ZIF

after

learning

and

retrieval

of

conditioned

fear

-LRB-

Fig.

-RRB-

These

reactivated

neurons

are

probably

projection

neurons

because

LAC

neurons

in

the

BLA

did

not

overlap

with

g-aminobutyric

acid

containing

neurons

-LRB-

fig

-RRB-

The

experiment

outlined

in

Fig.

used

four

groups

of

mice

The

home

cage

-LRB-

HC

-RRB-

group

remained

in

the

home

cage

throughout

the

experiment

the

fear-conditioning

-LRB-

FC

-RRB-

group

underwent

fear-conditioning

training

and

was

tested

for

retrieval

days

later

the

fear-conditioning

noretrieval

-LRB-

FC-NR

-RRB-

group

was

not

subjected

to

a

retrieval

test

and

the

no-shock

-LRB-

NS

-RRB-

group

was

treated

identically

to

the

FC

group

except

that

no

shocks

were

administered

The

FC

group

had

higher

freezing

-LRB-

lack

of

complete

movement

-RRB-

scores

during

context

retrieval

than

the

NS

group

-LRB-

Fig.

-RRB-

BLA

neurons

activated

during

learning

of

conditioned

fear

were

tagged

as

was

shown

by

the

higher

number

of

LAC-positive

neurons

in

the

combined

FC

groups

as

compared

with

those

in

both

the

HC

and

NS

groups

-LRB-

Fig.

-RRB-

This

increase

in

LAC

was

not

caused

by

retrievalinduced

activation

because

there

was

no

difference

between

the

FC

and

FC-NR

groups

-LSB-

t

-LRB-

-RRB-

-RSB-

We

next

asked

whether

neurons

activated

during

fear

conditioning

were

reactivated

during

retrieval

No

significant

differences

in

the

number

of

ZIF

neurons

were

found

-LRB-

-RRB-

however

the

FC

group

had

a

higher

number

of

LAC+ZIF

positive

neurons

than

the

HC

and

NS

groups

-LRB-

Fig.

-RRB-

Only

the

FC

group

showed

overlapping

expression

that

was

significantly

higher

than

expected

by

chance

-LRB-

Fig.

-RRB-

After

normalizing

for

chance

overlap

the

FC

group

had

more

LAC+ZIF

neurons

than

the

HC

and

FC-NR

groups

-LRB-

Fig.

-RRB-

Does

the

strength

of

neuronal

reactivation

in

the

BLA

correlate

with

the

strength

of

the

memory

retrieval

We

used

extinction

to

weaken

the

expression

of

the

fear

memory

-LRB-

-RRB-

Two

groups

of

mice

were

used

The

FC

group

was

treated

identically

to

the

FC

group

from

the

previous

experiment

whereas

the

extinction

-LRB-

EX

-RRB-

group

was

subjected

to

extinction

trials

between

learning

and

retrieval

-LRB-

Fig.

-RRB-

Extinc

expression

level

LAC

ZIF

ZIF

days

fear

conditioning

doxycycline

retrieval

doxycycline

hour

dissection

darkfield

LAC

ZIF

LAC

ZIF

Fig.

-LRB-

A

-RRB-

A

protocol

was

designed

to

detect

repeated

activation

of

neurons

during

learning

and

retrieval

of

conditioned

fear

Learning

takes

place

in

the

absence

of

Dox

when

activation

of

neurons

triggers

long-lasting

expression

of

LAC

and

short-lasting

expression

of

immediate-early

genes

like

Zif/Egr

-LRB-

ZIF

-RRB-

Retrieval

takes

place

days

after

learning

in

the

presence

of

Dox

which

prevents

activation

of

the

molecular

feedback

loop

Dissection

of

brains

is

done

hour

after

retrieval

when

LAC

and

ZIF

can

be

used

as

indicators

of

learninginduced

and

retrieval-induced

activation

respectively

-LRB-

B

-RRB-

Example

of

LAC

and

ZIF

expression

in

BLA

neurons

of

a

mouse

that

was

subjected

to

the

protocol

described

in

-LRB-

A

-RRB-

The

yellow

square

in

the

left

darkfield

picture

marks

the

area

shown

in

the

three

immunostaining

pictures

Yellow

arrows

mark

neurons

that

express

both

LAC

and

ZIF

Scale

bar

mm

CA

central

amygdala

A

home

cage

days

home

cage

home

cage

-LRB-

HC

-RRB-

no

shock

-LRB-

NS

-RRB-

fear

conditioning

-LRB-

FC

-RRB-

fear

conditioning

no

retrieval

-LRB-

FC-NR

-RRB-

B

C

LAC

neurons

-LRB-

DAPI

-RRB-

no

shock

days

retrieval

fear

conditioning

days

retrieval

Freezing

-LRB-

-RRB-

fear

conditioning

days

home

cage

NS

FC

HC

NS

FC

FC-NR

doxycycline

doxycycline

Fig.

Reactivated

neurons

in

the

BLA

during

fear

conditioning

provide

a

stable

neural

correlate

of

associative

memory

-LRB-

A

-RRB-

Diagram

of

the

experimental

design

HC

n

mice

NS

n

mice

FC

n

mice

FC-NR

n

mice

-LRB-

B

-RRB-

The

FC

group

showed

more

freezing

than

the

NS

group

during

context

retrieval

-LSB-

t

-LRB-

-RRB-

P

-RSB-

-LRB-

C

-RRB-

The

combined

FC

and

FC-NR

group

had

an

increased

number

of

LAC-positive

neurons

as

compared

with

both

the

HC

and

NS

groups

-LRB-

P

-RRB-

-LRB-

D

-RRB-

The

FC

group

had

a

higher

number

of

LAC+ZIF

positive

neurons

than

the

HC

and

NS

groups

-LRB-

P

-RRB-

In

the

FC

group

but

not

the

other

three

groups

the

number

of

LAC+ZIF

neurons

was

higher

than

chance

level

-LSB-

FC

t

-LRB-

-RRB-

P

-RSB-

-LRB-

E

-RRB-

The

FC

group

had

more

LAC+ZIF

neurons

than

the

HC

and

FC-NR

groups

after

subtracting

chance

level

-LRB-

P

-RRB-

Data

in

-LRB-

C

-RRB-

to

-LRB-

E

-RRB-

are

percentages

of

total

neurons

as

determined

by

-LRB-

DAPI

-RRB-

staining

Means

SEM

are

shown

in

-LRB-

B

-RRB-

to

-LRB-

E

-RRB-

P

P

SCIENCE

D

LAC+ZIF

neurons

-LRB-

DAPI

-RRB-

LAC+ZIF

chance

neurons

-LRB-

DAPI

-RRB-

E

chance

chance

chance

HC

NS

FC

FC

NR

chance

HC

NS

FC

FC

NR

VOL

AUGUST

Downloaded

from

on

May

A

B

REPORTS

A

fear

conditioning

days

doxycycline

doxycycline

day

extinction

day

extinction

day

retrieval

extinction

-LRB-

EX

-RRB-

fear

conditioning

-LRB-

FC

-RRB-

retrieval

B

LAC+ZIF

neurons

-LRB-

DAPI

-RRB-

basolateral

amygdala

P

C

LAC+ZIF

neurons

-LRB-

DAPI

-RRB-

basolateral

amygdala

N.S.

freezing

context

-LRB-

-RRB-

freezing

tone

-LRB-

-RRB-

LAC+ZIF

neurons

-LRB-

DAPI

-RRB-

LAC+ZIF

neurons

-LRB-

DAPI

-RRB-

P

N.S.

freezing

context

-LRB-

-RRB-

freezing

tone

-LRB-

-RRB-

Fig.

The

number

of

reactivated

neurons

in

the

BLA

and

LA

correlates

with

the

strength

of

the

conditioned

fear

memory

-LRB-

A

-RRB-

Diagram

of

the

experimental

design

EX

n

mice

FC

n

mice

-LRB-

B

-RRB-

Within

the

EX

group

the

number

of

LAC+ZIF

neurons

in

the

BLA

correlated

with

freezing

during

context

retrieval

-LRB-

R

P

-RRB-

-LRB-

C

-RRB-

The

number

of

BLA

LAC+ZIF

neurons

did

not

correlate

with

the

estimated

freezing

during

tone

retrieval

-LRB-

R

P

-RRB-

N.S.

not

significant

Freezing

during

tone

retrieval

was

estimated

by

subtracting

the

freezing

before

the

first

tone

from

the

freezing

during

the

first

tone

-LRB-

D

-RRB-

In

the

LA

the

number

of

LAC+ZIF

neurons

did

not

correlate

with

freezing

during

context

retrieval

-LRB-

R

P

-RRB-

-LRB-

E

-RRB-

In

the

LA

there

was

a

significant

correlation

between

the

number

of

LAC+ZIF

neurons

and

the

estimated

freezing

during

tone

retrieval

-LRB-

R

P

-RRB-

tion

resulted

in

a

significant

decrease

in

fearmemory

expression

as

indicated

by

freezing

during

context

retrieval

-LSB-

EX

freezing

due

to

context

retrieval

FC

t

-LRB-

-RRB-

P

-RSB-

The

EX

and

FC

groups

had

similar

numbers

of

LAC

ZIF

or

LAC+ZIF

neurons

in

the

BLA

-LRB-

and

respectively

-RRB-

However

extinction

showed

variable

effectiveness

in

individual

mice

with

freezing

scores

ranging

from

to

This

result

allowed

us

to

look

for

a

correlation

within

a

group

of

similarly

treated

mice

between

the

strength

of

-LRB-

behaviorally

expressed

-RRB-

conditioned

fear

and

the

number

of

reactivated

neurons

Within

the

EX

group

there

was

a

strong

correlation

between

the

number

of

LAC+ZIF

neurons

and

the

freezing

score

measured

during

context

retrieval

-LRB-

Fig.

-RRB-

There

was

no

correlation

with

LAC

alone

-LRB-

R

P

-RRB-

or

ZIF

alone

-LRB-

R

P

-RRB-

Training

extinction

and

retrieval

used

both

the

context

and

a

tone

as

conditioned

stimuli

-LRB-

CS

-RRB-

so

that

neuronal

correlates

of

both

memories

could

be

examined

Freezing

scores

shown

in

Fig.

were

obtained

during

the

beginning

of

the

retrieval

test

before

the

first

tone

and

thus

indicated

contextual

fear

memory

We

obtained

an

estimate

of

the

strength

of

the

tone

fear

memory

by

subtracting

the

freezing

before

the

first

tone

from

the

freezing

during

the

first

tone

There

was

no

correlation

between

the

estimated

freezing

during

tone

retrieval

and

the

number

of

reactivated

neurons

in

the

BLA

-LRB-

Fig.

-RRB-

However

the

number

of

reactivated

neurons

in

the

lateral

amygdala

-LRB-

LA

-RRB-

correlated

with

the

estimated

freezing

during

tone

retrieval

but

did

not

correlate

with

the

freezing

during

context

retrieval

-LRB-

Fig.

D

and

E

-RRB-

We

localized

a

group

of

neurons

in

the

amygdala

that

was

activated

during

learning

and

reactivated

during

retrieval

of

a

fear

memory

Reactivation

of

neurons

in

the

BLA

and

LA

correlated

with

contextual

and

tone

fear

memory

respectively

which

is

in

accordance

with

previous

studies

-LRB-

-RRB-

The

reactivated

neurons

did

not

simply

respond

to

the

repeated

pattern

of

VOL

SCIENCE

References

and

Notes

J.

O'Keefe

Exp

Neurol

-LRB-

-RRB-

G.

R.

Sutherland

B.

McNaughton

Curr

Opin

Neurobiol

-LRB-

-RRB-

R.

F.

Thompson

Annu

Rev.

Psychol

-LRB-

-RRB-

T.

Sigurdsson

V.

Doyere

C.

K.

Cain

J.

E.

LeDoux

Neuropharmacology

-LRB-

-RRB-

J.

M.

Fuster

Neuron

-LRB-

-RRB-

J.

Radulovic

J.

Kammermeier

J.

Spiess

J.

Neurosci

-LRB-

-RRB-

J.

Hall

K.

L.

Thomas

B.

J.

Everitt

J.

Neurosci

-LRB-

-RRB-

W.

P.

Zhang

J.

F.

Guzowski

S.

A.

Thomas

Learn

Mem

-LRB-

-RRB-

AUGUST

Downloaded

from

on

May

D

lateral

amygdala

E

lateral

amygdala

CS

-LRB-

i.e.

context

and

tone

-RRB-

because

the

unconditioned

stimulus

-LRB-

US

-RRB-

-LRB-

i.e.

shock

-RRB-

was

required

during

learning-induced

activation

but

not

during

retrieval-induced

reactivation

Hebbian

models

of

plasticity

postulate

that

synaptic

weight

changes

should

occur

at

synapses

that

are

active

concurrently

with

neuronal

firing

In

fear

conditioning

this

should

occur

at

neurons

that

receive

both

CS

and

US

inputs

such

that

the

enhanced

strength

of

the

CS

inputs

produced

by

Hebbian

plasticity

would

allow

firing

-LRB-

or

increased

rates

of

firing

-RRB-

of

conditioning-activated

neurons

in

response

to

the

CS

presentation

alone

during

the

retrieval

trial

This

reactivation

would

in

effect

recapitulate

aspects

of

the

original

learning

episode

In

the

FC

group

of

the

neurons

tagged

with

LAC

were

reactivated

during

retrieval

-LRB-

Fig.

C

and

D

-RRB-

The

nonreactivated

LAC

cells

would

represent

either

neurons

activated

in

the

home

cage

-LRB-

as

observed

in

the

HC

group

in

Fig.

-RRB-

or

USstimulated

neurons

that

did

not

receive

CS

inputs

during

learning

and

were

therefore

not

reactivated

during

retrieval

Previous

studies

found

neurons

in

the

BLA

and

LA

that

receive

convergent

projections

from

CS

and

US

pathways

and

that

can

undergo

fear

conditioning

induced

Hebbian

plasticity

that

lasts

for

several

hours

-LRB-

-RRB-

The

current

result

suggests

that

this

plasticity

evolves

into

stable

synaptic

changes

that

confer

on

these

neurons

a

capacity

for

reactivation

by

the

CS

that

lasts

for

at

least

days

The

reactivated

neurons

seem

to

be

a

likely

component

of

a

stable

engram

or

memory

trace

for

conditioned

fear

The

TetTag

mouse

provides

a

distinctive

tool

for

localizing

memories

in

a

complex

neuronal

network

It

combines

the

ability

to

image

all

the

neurons

in

the

region

of

interest

with

the

ability

to

assess

activation

of

the

same

neuron

at

widely

separate

time

points

Because

reactivation

of

neurons

takes

place

in

freely

moving

mice

it

can

be

correlated

with

the

behavioral

expression

of

the

memory

Use

of

the

TetTag

mouse

only

requires

basic

immunohistochemistry

and

microscopy

tools

which

are

available

to

most

researchers

The

TetTag

mouse

not

only

provides

a

tag

through

the

expression

of

a

reporter

gene

but

can

also

drive

the

expression

of

additional

transgenes

that

can

be

used

to

both

follow

and

manipulate

the

physiology

of

the

tagged

neurons

-LRB-

-RRB-

REPORTS

J.

F.

Guzowski

et

al.

Curr

Opin

Neurobiol

-LRB-

-RRB-

Materials

and

methods

are

available

as

supporting

material

on

Science

Online

R.

J.

Smeyne

et

al.

Neuron

-LRB-

-RRB-

M.

Gossen

et

al.

Science

-LRB-

-RRB-

M.

Mayford

et

al.

Science

-LRB-

-RRB-

J.

J.

Kim

M.

S.

Fanselow

Science

-LRB-

-RRB-

R.

G.

Phillips

J.

E.

LeDoux

Behav

Neurosci

-LRB-

-RRB-

S.

Maren

M.

S.

Fanselow

J.

Neurosci

-LRB-

-RRB-

L.

Calandreau

A.

Desmedt

L.

Decorte

R.

Jaffard

Learn

Mem

-LRB-

-RRB-

L.

Calandreau

et

al.

J.

Neurosci

-LRB-

-RRB-

K.

M.

Myers

M.

Davis

Mol

Psychiatry

-LRB-

-RRB-

S.

Maren

Annu

Rev.

Neurosci

-LRB-

-RRB-

G.

J.

Quirk

C.

Repa

J.

E.

Ledoux

Neuron

-LRB-

-RRB-

F.

Zhang

et

al.

Nature

-LRB-

-RRB-

We

thank

S.

G.

Anagnostaras

for

critical

reading

of

the

manuscript

and

K.

Spencer

T.

Y.

Pan

and

D.

Fang

for

excellent

technical

assistance

This

work

was

supported

by

the

NIH

-LRB-

National

Institute

of

Mental

Health

grants

and

-RRB-

Supporting

Online

Material

Materials

and

Methods

Figs

to

References

April

accepted

July

science

Land-Use

Allocation

Protects

the

Peruvian

Amazon

Paulo

J.

C.

Oliveira

Gregory

P.

Asner

David

E.

Knapp

Ang

lica

Almeyda

Ricardo

Galv

n-Gildemeister

Sam

Keene

Rebecca

F.

Raybin

Richard

C.

Disturbance

and

deforestation

have

profound

ecological

and

socioeconomic

effects

on

tropical

forests

but

their

diffuse

patterns

are

difficult

to

detect

and

quantify

at

regional

scales

We

expanded

the

Carnegie

forest

damage

detection

system

to

show

that

between

and

disturbance

and

deforestation

rates

throughout

the

Peruvian

Amazon

averaged

square

kilometers

per

year

and

square

kilometers

per

year

respectively

However

only

to

occurred

within

natural

protected

areas

indigenous

territories

contained

only

of

the

forest

disturbances

and

of

the

deforestation

and

recent

forest

concessions

effectively

protected

against

clear-cutting

Although

the

region

shows

recent

increases

in

disturbance

and

deforestation

rates

and

leakage

into

forests

surrounding

concession

areas

land-use

policy

and

remoteness

are

serving

to

protect

the

Peruvian

Amazon

T

ropical

forests

play

essential

roles

in

ecological

climate

and

biogeochemical

processes

and

in

the

lives

of

human

populations

-LRB-

-RRB-

but

anthropogenic

disturbances

can

disrupt

forest

structure

function

and

composition

-LRB-

-RRB-

Because

of

its

large

relatively

contiguous

area

of

primary

rainforest

the

Peruvian

Amazon

has

major

conservation

value

and

is

considered

a

priority

in

nearly

all

global

biodiversity

inventories

-LRB-

-RRB-

Despite

the

internationally

recognized

uniqueness

and

importance

of

Peruvian

rainforest

ecosystems

the

impacts

of

human

activities

throughout

the

region

remain

poorly

understood

Increasing

rates

of

large-scale

forest

damage

in

the

neighboring

Brazilian

Amazon

have

been

linked

to

modern

road

building

and

government

policies

supporting

resource

extraction

and

settlement

-LRB-

-RRB-

Peru

's

of

Amazon

tropical

forest

are

also

subject

to

elevated

human

impacts

that

have

not

been

well

documented

at

the

landscape

level

The

paving

of

the

InterOceanic

Highway

and

the

spreading

road

network

throughout

the

Pucallpa

region

have

brought

Department

of

Global

Ecology

Carnegie

Institution

of

Washington

Stanford

CA

USA

of

Anthropological

Sciences

Stanford

University

Stanford

CA

USA

del

Bien

Com

n

Avenida

Petit

Thouars

Miraflores

Lima

Per

of

Electrical

and

Computing

Engineering

Boston

University

Saint

Mary

's

Street

Boston

MA

USA

To

whom

correspondence

should

be

addressed

E-mail

gpa@stanford.edu

migrants

mostly

from

the

Peruvian

Andes

along

with

largely

undocumented

impacts

on

forest

cover

and

structure

However

in

recent

years

the

Peruvian

government

has

also

established

or

extended

large

natural

protected

areas

and

indigenous

territories

in

the

Peruvian

Amazon

and

forest

management

legislation

has

placed

of

its

forests

into

permanent

resource

production

status

-LRB-

table

-RRB-

of

which

went

into

long-term

timber-producing

commercial

concessions

by

-LRB-

-RRB-

Small-scale

studies

have

noted

an

increase

in

forest

damage

within

some

protected

areas

mostly

as

a

result

of

land

conversion

to

agriculture

and

pasture

near

human

settlements

and

river

valleys

-LRB-

-RRB-

associated

with

proximity

to

roads

rural

credit

programs

and

access

to

markets

-LRB-

-RRB-

as

well

as

inadequate

landuse

planning

and

governance

-LRB-

-RRB-

However

a

synoptic

assessment

of

forest

disturbance

and

deforestation

has

not

been

derived

for

Peruvian

forests

Large-scale

assessments

of

forest

disturbance

in

the

Peruvian

Amazon

typically

diffuse

and

difficult

to

detect

require

complex

detection

algorithms

for

the

analysis

of

high-resolution

satellite

imagery

-LRB-

-RRB-

but

these

methods

are

just

now

proving

critical

for

land

management

conservation

analysis

and

land-use

policy

assessments

in

tropical

forest

regions

-LRB-

-RRB-

We

adapted

a

satellite-based

forest

disturbance

detection

system

originally

designed

for

industrial-grade

timber

extraction

monitoring

in

Brazil

to

Peru

's

generally

smaller-scale

forest

disturbance

regimes

We

SCIENCE

VOL

Table

Forest

disturbance

and

deforestation

area

estimates

for

Peruvian

Amazon

tropical

forest

based

on

CLAS

methodology

The

number

of

satellite

paths

per

rows

in

each

year

varied

according

to

image

availability

There

were

path/row

in

in

and

in

On

the

basis

of

an

assessment

of

the

spatial

distribution

of

forest

damage

in

the

first

years

a

subset

of

satellite

path/row

was

selected

for

analyses

in

the

following

years

as

available

path/row

in

in

and

in

Year

Mean

Damage

rates

-LRB-

km

year

-RRB-

Disturbed

Deforested

653 617 508 409

546 1070 634 731

698 616 470 192

AUGUST

Downloaded

from

on

May

present

an

updated

version

of

the

Carnegie

Landsat

Analysis

System

-LRB-

CLAS

stanford.edu

-RRB-

and

applied

it

to

a

study

area

covering

of

the

Peruvian

Amazon

-LRB-

-RRB-

from

to

The

core

technology

of

the

CLAS

change-detection

algorithm

-LRB-

-RRB-

was

improved

with

optimized

automated

versions

of

the

atmospheric

and

haze

correction

and

the

water

and/or

cloud-masking

processes

of

the

Monte

Carlo

unmixing

-LRB-

AutoMCU

-RRB-

approach

-LRB-

-RRB-

We

also

added

an

automated

deforestationdetection

component

to

provide

an

integrated

analysis

of

both

diffuse

forest

disturbance

and

clear-cutting

We

used

Landsat

TM

-LRB-

Thematic

Mapper

-RRB-

and

Landsat

ETM

-LRB-

Enhanced

Thematic

Mapper

Plus

-RRB-

satellite

images

at

a

spatial

resolution

of

m

by

m

to

derive

annual

incremental

damage

maps

for

most

of

the

human-impacted

timber-producing

regions

up

to

images

per

year

with

each

nonoverlapping

footprint

covering

The

satellite

detection

results

were

validated

via

a

large

field

survey

in

the

Pachitea

and

Ucayali

watershed

regions

and

regionally

evaluated

against

available

land

use

land

cover

and

conservation

maps

We

found

that

and

of

Peruvian

Amazon

forests

were

subjected

to

new

forest

disturbances

and

O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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