Many neurological diseases such as dementia, including Alzheimer's disease, stroke, depression, Parkinson's disease and motor neuron disease are associated with a reduction in the number of neurons. The decline in number of neurons may be rapid, as in the case of stroke, or slower, as in the case of Alzheimer's disease.
After heart disease and cancer, stroke is the third leading cause of death in western industrialized countries and the major cause of severe, long-term disability in adults with 56% of people following a stroke suffering from a severe or profound disability. There are over 20 million stroke survivors worldwide. This ailment represents an economic burden estimated to be $45 billion a year in the US alone and is expected to rise significantly. A significant factor contributing to this trend is the increased susceptibility to stroke among the elderly.
Alzheimer's disease is the most common dementia occurring in the elderly, affecting about 10% of people above 65 years and 40% above 80 years. Alzheimer's is predicted to afflict up to 16 million people by the middle of this century unless a cure or prevention is found in the United States alone. 50-75% of dementia is estimated to be caused by Alzheimer's disease. The prevalence of Alzheimer's disease is slightly higher in women than in men, but almost twice as many women live with dementia because of their longer life expectancy.
Alzheimer's disease is a progressive neurodegenerative disease characterized by memory loss and general cognitive and behavioural decline. Alzheimer's disease is commonly associated with a non-cognitive symptomatology including depression. Histologically, Alzheimer's disease is defined by the presence in post-mortem human brain specimens of amyloid neuritic plaques, the formation of neurofibrillary tangles and degeneration of the cholinergic neurons.
Parkinson's disease is associated with the destruction of neurons, but the damage is restricted to the dopamine-producing cells in the substantia nigra (part of the basal ganglia). The most common symptoms of Parkinson's disease are tremor, rigidity and difficulty initiating movement. In the US alone, some one million patients are affected and 50,000 new patients are added annually.
Depression is one of the most common mental disorders in the community. In Australia one in four women and one in six men will experience depression at some time in their life. Depression presents with depressed mood and loss of interest or pleasure. It affects about 121 million people worldwide.
Motor neuron disease is the name given to a group of diseases in which nerve cells that control the muscles degenerate and die. It is rarely diagnosed in people less than 30 years of age. In Australia, there are around 400 new cases of motor neuron disease each year. There is no effective method of treatment and the disease is generally fatal within 1-5 years of diagnosis. More than one person dies of Motor neuron disease each day in Australia.
There are several regions in the brain where stem cells are known to exist, including the sub-ventricular zone and the hippocampus. It is thought that the stem cells in these areas are already working at maximum capacity to generate new neurons for general “self-maintenance”.
The adult mammalian hippocampus harbours neural precursors that reside and proliferate in the milieu of the neurogenic niche (Ming, 2005). These precursors differentiate into neurons that functionally integrate into the hippocampal neurocircuitry, thereby influencing functions such as learning and memory (Lledo, 2006). Elucidating the regulatory mechanisms to enhance this form of cellular plasticity has been a major focus in recent years, driven by the need to combat neurodegenerative disorders such as Alzheimer's disease and stroke, as well as psychiatric diseases including depression.
Accumulating evidence has suggested an important role for synaptic activity in regulating the process of adult hippocampal neurogenesis (Ming, 2005 and Zhao, 2008). Neural excitation has been shown to activate a latent stem cell pool (Walker, 2008), to promote precursors to commit to a neurogenic fate (Deisseroth, 2004), as well as to enhance the survival and integration of newly born neurons in the adult hippocampus (Ge, 2006 and Tashiro, 2006). Amongst the factors that are released following synaptic activity are the neurotransmitters, trophic roles for which are increasingly being appreciated in the regulation of neurogenesis (Hagg, 2009 and Vaidya (2007). Recent studies have shown that glutamate and GABA receptors are present on a subset of adult hippocampal precursors and regulate their proliferation (Ge, 2006, Ge, 2007 and Nacher, 2007). However, their role in directly activating a latent precursor population has been ruled out (Walker, 2008).
Within the monoaminergic neurotransmitter family, a large number of in vivo studies have focused on the roles of serotonin and norepinephrine, revealing a strong correlation between their levels and the extent of hippocampal neurogenesis (Brezun, 1999, Kulkarni, 2002 and Brezun, 2000) Furthermore, impaired neurogenesis has been demonstrated in animal models of stress and depression (Malberg, 2003 and Vollmayr, 2007), where a significant reduction in the levels of serotonin and norepinephrine are also commonly observed (Vaidya, 2007 and Charney, 1998). In agreement with these lines of evidence, pharmacological agents, such as antidepressants that act by elevating levels of serotonin and norepinephrine, have been shown to enhance hippocampal neurogenesis (Malberg, 2000). Similarly, studies utilizing pharmacological lesions have proposed a proliferative role for norepinephrine, although controversy still exists regarding the role of serotonin in regulating the proliferation of hippocampal precursors (Kulkarni, 2002, Jha, 2006 and Huang, 2006). However, one of the limitations of the current in vivo approaches is the inability to dissect out direct versus non-cell-autonomous effects of these neurotransmitters on the precursor population. Whether serotonin or norepinephrine has a direct effect on adult hippocampal precursors, and the cellular and molecular identity of such a precursor population, therefore was hitherto unknown.