Shawn Sorrells - US grants

DESCRIPTION (provided by applicant): Glucocorticoids (GCs) are hormones released from the adrenal glands during stress and are well known for their potent and pleiotropic anti-inflammatory effects. In the injured CNS, their anti-inflammatory properties could be beneficial in cases where excessive inflammation imperils neuron survival. It is therefore important to understand specifically how GCs affect the immune response in the brain, especially given emerging evidence that under some circumstances GCs do not decrease inflammation and can even augment aspects of the immune response during CMS injury. It is well established that acute GC exposure can augment localized inflammatory responses while longer-term GC exposure is immunosuppressive. However, chronic GC exposure was recently found to increase CMS infiltration of macrophages, granulocytes, and microglia to excitotoxic injury accompanied by elevated levels of the pro-inflammatory cytokines IL-1(i, TNF-a, and IL-6. Chronic GC exposure was also found to augment CMS signaling of these cytokines and the pro-inflammatory transcription factor NFicB from peripheral exposure to endotoxin. Given their well-known anti-inflammatory properties, it is surprising that GCs do not blunt, but instead increase these inflammatory responses. Based on these findings, it is possible that chronic exposure to GCs augments the inflammatory response in the injured CMS. Chronic GC exposure could elevate CNS inflammation by stimulating any of the GC receptor subtypes in any of the cells present in the CNS. Two different nuclear hormone receptors for GCs exist, namely the GC receptor (GR) and the mineralocorticoid receptor (MR). A GR antagonist blocks the GC-augmented CNS inflammation, implicating the GR in this phenomenon;however it is unclear which cell type(s) are acted on by GCs to cause these pro-inflammatory effects. The most likely neuro-immune targets of GCs are the resident microglia and the peripheral leukocytes that extravasate to the site of injury. Both of these cell types express GR and are instrumental in orchestrating immune responses to acute injury. This proposal is designed to measure immune cell-specific effects of GCs during kainic acid-induced excitotoxicity by using previously characterized leukocyte-specific, GR-knockout mice. We will test the hypothesis that GR signaling in leukocytes is necessary for their increased recruitment and activation. We will also determine whether GR signaling in these cells affects the likelihood of neuron survival. The following aims are proposed to determine which of the observed effects of chronic GCs on inflammation and neuron death can be explained by leukocyte cell-autonomous GR signaling:

DESCRIPTION (provided by applicant): 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.

Project Summary The amygdala is a major processing center for emotional and social behaviors, aspects of which are altered in developmental disorders such as Autism Spectrum Disorders (ASD). In humans, the paralaminar nucleus of the amygdala (PL), located adjacent to basolateral amygdala amygdala (BLA), contains a large population of immature neurons that persist into post-natal stages, well past the maturational time course of the overwhelming majority of neurons in the brain. Our recent studies have revealed that human PL neurons mature prominently during childhood and adolescence (Sorrells et al., Nature Communications, 2019). This raises the intriguing possibility that these neurons are essential for social/emotional changes that occur during critical periods of postnatal development. Our preliminary data reveal that this population is also present in mice. This opens up an exciting opportunity to use the mouse to model this interesting neuronal population. The goals of this exploratory R21 application are to: 1) characterize the post-natal morphological, molecular and electrophysiological maturational profiles of mouse PL neurons during the pre-pubertal critical period temporally coinciding with emergence of emotional processing in humans and 2) determine the developmental timing and origin of mouse PL neurons. As embryonic origin and identity are intimately tied to adult neuronal function, these studies are also a important first step to ultimately dissecting neural connectivity, function and role that these specialized cells play in neuro-typical and -atypical social-emotional development.