The majority of the local-circuit neurons (interneurons) in the forebrain produce the inhibitory neurotransmitter GABA. Interneurons are essential for excitatory-inhibitory balance in cortical and hippocampal circuits and play key roles in neural circuit plasticity and function. In the amygdala, multiple types of interneurons are critical to normal circuit function and plasticity, and changes within these cells and their connectivity may underlie imbalances that produce pathological fear, anxiety, and depressed behaviors, like those seen in post-traumatic stress disorder. Embryonic precursor cells that give rise to inhibitory interneurons can be grafted postnatally (into juvenile and adult rodents) where these cell migrate and integrate into existing functional circuits. The grafted precursor cells als differentiate into specific subtypes of interneurons that can re- establish inhibitory balance or r-open critical period plasticity. This form of neural circuit modification has great potential in th treatment of disease, yet the possibility of modifying amygdala circuitry by interneuron transplantation has not been explored. Interneuron transplants could help to restore the balance of synaptic networks that is pathologically disrupted in the amygdala in post-traumatic stress disorder and depression. In this proposal I will test the hypothesis that pathological changes (either inherited or acquired) in amygdala interneuron function can be reversed by bringing new interneurons into the circuit. I have preliminary data showing that precursor cells transplanted into the adult amygdala become interneurons and can persist with healthy morphology for at least seven months post-transplant. Furthermore, transplanted animals do not suffer from any behavioral side-effects in motor function, activity levels, non-spatial memory learning and recall, nociception, or food intake patterns. In addition, I have developed an animal model that is lacking parvalbumin+ interneurons in the basolateral amygdala and has the inability to acquire either cued or contextual fear memory during fear conditioning. Using this preliminary work, I will test in Aim (1) the ability of inhibitory interneuron precursor transplants to integrate into and restore the behavioral function in the parvalbumin-deficient mice.
In Aim (2) I will determine which cells the transplanted interneurons form synapses with and I will compare that to the endogenous connectivity of interneurons. Finally, in Aim (3) I will test whether pharmacological acute-inactivation or acute-activation of only the transplanted cells can further modify the behavior of the host animal.
The abnormal function of inhibitory interneurons may contribute to many neuropsychiatric disorders, so the development of new therapeutic strategies hinges on a better understanding of the role of these cells in animal behavior. This project will study how inhibitory interneuron precursor cells that are transplanted into the normal adult mouse brain successfully integrate into and modify the existing neuronal circuitry. Additionally, this work will test the ability of these transplants to restore normal behavior in mice that have behavioral deficits resulting from the lack of specific subtypes of interneurons.
|Sorrells, Shawn F; Paredes, Mercedes F; Cebrian-Silla, Arantxa et al. (2018) Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature 555:377-381|
|Paredes, Mercedes F; Sorrells, Shawn F; Garcia-Verdugo, Jose M et al. (2016) Brain size and limits to adult neurogenesis. J Comp Neurol 524:646-64|
|Vogt, Daniel; Wu, Pei-Rung; Sorrells, Shawn F et al. (2015) Viral-mediated Labeling and Transplantation of Medial Ganglionic Eminence (MGE) Cells for In Vivo Studies. J Vis Exp :|