The long-term objective of this training and research award is to enable the candidate to establish an independent research program that integrates mouse genetics with behavioral neuroscience to understand how neural circuits are substrates for etiological mechanisms and treatment of psychiatric illnesses. The mentored phase of this award will complement the candidate's extensive background experience in developmental neurobiology, molecular biology and mouse genetics with a rigorous training in behavioral neuroscience as applied to the study of cognition and emotion in mice. The research proposal is predicated upon growing evidence that implicates adult hippocampal neurogenesis as necessary for specific forms of learning and mediating some of the behavioral effects of antidepressants.
The Specific Aims address how adult hippocampal neurogenesis may be harnessed to enhance learning and modulate mood. Through the use of novel genetic gain-of-function strategies with which discrete components of adult neurogenesis can be enhanced in a cell-autonomous manner, the candidate will test if increasing the number or enhancing the maturation of adult-born neurons is sufficient to enhance learning and confer the behavioral effects of antidepressants. These experiments will reveal how adult born neurons contribute to pattern separation, a fundamental feature of encoding in the dentate gyrus, and to the functions of the dentate gyrus in mood regulation. From a translational standpoint, these experiments will help determine the therapeutic impact of stimulating discrete components of adult hippocampal neurogenesis to reverse cognitive deficits and for treatment of depression. To accomplish these goals, the candidate has developed a plan that combines extensive practical training in behavioral neuroscience with formal mentorship, consultations with experienced investigators and relevant coursework. The training program will also enable the candidate to acquire a framework in translational neuroscience so as to continue to develop and test novel hypotheses that are grounded in basic neuroscience and relevant to the study of mental illnesses.
The proposed research will help determine the therapeutic impact of stimulating adult hippocampal neurogenesis for ameliorating cognitive impairments in psychiatric disorders and for treatment of depression. It may result in the development of fast acting novel treatments for depression and cognitive deficits that target discrete components of adult hippocampal neurogenesis and are encumbered by fewer side-effects.
|Sahay, Amar; Wilson, Donald A; Hen, Rene (2011) Pattern separation: a common function for new neurons in hippocampus and olfactory bulb. Neuron 70:582-8|
|Sahay, Amar; Scobie, Kimberly N; Hill, Alexis S et al. (2011) Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature 472:466-70|
|Scobie, Kimberly N; Hall, Benjamin J; Wilke, Scott A et al. (2009) Krüppel-like factor 9 is necessary for late-phase neuronal maturation in the developing dentate gyrus and during adult hippocampal neurogenesis. J Neurosci 29:9875-87|