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Chalmers, N. E.

Publications and source records attributed to Chalmers, N. E..

2 recordsLinked to original sources
bioRxiv2025

Endogenous recovery of hippocampal function following global cerebral ischemia in juvenile female mice is influenced by neuroinflammation and circulating sex hormones.

Cardiac arrest-induced global cerebral ischemia (GCI) in childhood often results in learning and memory deficits. We previously demonstrated in a murine cardiac arrest and cardiopulmonary resuscitation (CA/CPR) mouse model that a cellular mechanism of learning and memory, long-term potentiation (LTP), is acutely impaired in the hippocampus of juvenile males, correlating with deficits in memory tasks. However, little is known regarding plasticity impairments in juvenile females. We performed CA/CPR in juvenile (P21-25) female mice and used slice electrophysiology and hippocampal dependent behavior to assess hippocampal function. LTP was and contextual fear were impaired 7-days after GCI and endogenously recovered by 30-days. LTP remained impaired at 30 days in ovariectomized females, suggesting the surge in gonadal sex hormones during puberty mediates endogenous recovery. Unlike juvenile males, recovery of LTP in juvenile females was not associated with BDNF expression. NanoString transcriptional analysis revealed a potential role of neuroinflammatory processes, and specifically Cd68 pathways, in LTP impairment and hormone-dependent recovery. We were able to restore LTP in ovariectomized females with chronic and acute PPT administration, implicating estrogen receptor alpha in recovery mechanisms. This study supports a mechanism of endogenous LTP recovery after GCI in juvenile female mice which differs mechanistically from juvenile males and does not occur in adults of either sex.

neuroscience↗
bioRxiv2025

Enhanced Calcium Signaling in BLA Pyramidal Neurons Underlies a Sex and Circuit Specific Amygdala Dysfunction After Global Cerebral Ischemia

While advances in resuscitation science have improved cardiac arrest survival, we lack therapies to improve cognitive-affective outcomes in this patient population. Our lab has previously identified cognitive dysfunction in a mouse model of global cerebral ischemia (GCI) which has been attributed to hippocampal neurodegeneration and impaired hippocampal plasticity. However, no study has attempted to identify amygdala dysfunction after GCI, despite clinical evidence of emotional dysfunction, such as anxiety and Post-Traumatic Stress Disorder (PTSD). Therefore, it is important to identify the effect that GCI has on the amygdala, the emotional center of the brain. Our lab has a well-developed, translatable mouse model of GCI, the cardiac arrest/cardiopulmonary resuscitation model (CA/CPR), that has been instrumental in assessing amygdala function after GCI. We have utilized the amygdala-dependent delay-fear conditioning (DFC) paradigm to assess associative learning and memory and have performed field excitatory post-synaptic potential (fEPSP) recordings in two circuits within the amygdala, as measures of amygdala function. We have found a sex- and circuit-specific deficit in LTP of the cortical input to the basolateral amygdala (BLA), after GCI, that corresponds with a male specific associative learning and memory deficit. We found no evidence that these deficits of amygdala function can be attributed to GCI-induced neurodegeneration within the amygdala or altered locomotor function. We did, however, find that neuronal dendritic spine calcium signaling dynamics are enhanced in male survivors of GCI and are likely contributing to the observed LTP deficit and ultimately the deficit in associative learning and memory processes. Significance StatementWhile cognitive dysfunction has been well characterized in CA/CPR survivors, the development of emotional dysfunction that may arise in survivors is understudied. Poor follow up of CA/CPR survivors has left a gap in our knowledge about the effect that GCI has on the amygdala, the emotional center of the brain. Thus, this study utilized a pre-clinical mouse model of CA/CPR to characterize amygdala dysfunction that arises from GCI. We found a male-specific deficit in associative learning and memory that corresponds with a circuit specific LTP deficit, which arises from elevated calcium signaling in dendritic spines. Thus, this study provides valuable information and rationale for extended follow up of CA/CPR survivors to identify and treat the development of GCI-induced affective disorders.

neuroscience↗