Biology subjects

Herson, P. S.

Publications and source records attributed to Herson, P. S..

7 recordsLinked to original sources

bioRxiv2025

Modeling interaction between focal cerebral ischemia and Alzheimer`s Disease Pathology in an APP/PS1 Mouse Model

Ischemic stroke is one of the leading causes of death and disability in the United States and is a known risk factor for Alzheimers Disease (AD) development. One of the characteristics of AD is the accumulation of {beta}-amyloid peptide due to the proteolysis of Amyloid Precursor Protein (APP) by the protein Presenilin 1 (PS1). The study of interaction between ischemia and AD has been limited due to lack of experimental models. The current study describes a novel model utilizing a brief transient ischemia (15 min MCAO) in an AD mouse model to assess mechanistic interaction. Here we investigate the effects of increased {beta}-amyloid peptide on motor coordination, behavioral and cellular memory, when subjected to brief focal ischemia. APP/PS1 or Wt male mice are initially subjected to either a 15-minute MCAO or Sham surgery. Injury volume using MRI is assessed at 3-days using T2 imaging and demonstrates that injury magnitude was not different between Wild-type and APP/PS1 mice. We observed that 15 min MCAO did not cause significant motor deficits in either WT or APP/PS1 mice, as measured by open field and tapered balance beam. Short-term memory was assessed 7 days after recovery from brief MCAO using the contextual fear conditioning task. APP/PS1 mice exhibited intact memory at 3 months of age and Wt mice also having intact memory 7 days after 15 min MCAO. In contrast, APP/PS1 + 15 min MCAO mice exhibited a significant reduction in freezing behavior suggesting impairment in short term memory. Consistent with our contextual fear conditioning, we observed impaired hippocampal long-term potentiation (LTP) in APP/PS1 + 15 min MCAO compared to their sham counterparts. Remarkably, we observed an additive effect of ischemia and AD, with cellular and behavior memory deficits observed in APP/PS1 mice exposed to brief ischemia that does not cause symptoms in WT mice. This study represents an important new model to be study the mechanistic link between ischemia and accelerated AD progression.

neuroscience↗

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↗

bioRxiv2023

TRPM2-CaMKII signaling drives excessive GABAergic synaptic inhibition following ischemia

Following an ischemic insult to the brain, there is an acute loss of GABAergic inhibitory synapses and an increase in excitatory/ inhibitory (E/I) imbalance that drives neuronal hyperexcitability. It is unknown whether this E/I imbalance persists at delayed timepoints and contributes to chronic impairments in memory and long-term potentiation (LTP) in the hippocampus following ischemic brain injury. Here, we reveal a shift to reduced E/I ratio in hippocampal CA1 neurons via a persistent increase in postsynaptic GABAA receptor mediated inhibitory responses and clustering days after a global ischemic insult. This enhancement of postsynaptic inhibitory function and clustering required activation of the Ca2+-permeable TRPM2 ion channel and the Ca2+-dependent kinase, CaMKII. Thus, we propose a mechanism in which acute downregulation of GABAA receptors is followed by a strengthening of inhibitory synapses at delayed periods after ischemia. Targeting this mechanism has therapeutic potential to recover hippocampal plasticity and cognitive function post-ischemia. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=123 SRC="FIGDIR/small/556550v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@16ef5f2org.highwire.dtl.DTLVardef@1d51f19org.highwire.dtl.DTLVardef@ecc726org.highwire.dtl.DTLVardef@106cdd0_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Short-term CaMKII inhibition with tatCN19o does not erase pre-formed memory and is neuroprotective in non-rodents

The Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a central regulator of learning and memory, which poses a problem for targeting it therapeutically. Indeed, our study supports prior conclusions that long-term interference with CaMKII signaling can erase pre-formed memories. By contrast, short-term pharmacological CaMKII inhibition with tatCN19o interfered with learning in mice only mildly and transiently (for less than 1 h) and did not at all reverse pre-formed memories. This was at [≥]500fold of the dose that protected hippocampal neurons from cell death after a highly clinically relevant pig model of transient global cerebral ischemia: ventricular fibrillation followed by advanced life support and electrical defibrillation to induce return of spontaneous circulation. Of additional importance for therapeutic development, cardiovascular safety studies in mice and pig did not indicate any concerns with acute tatCN19o injection. Taken together, even though prolonged interference with CaMKII signaling can erase memory, acute short-term CaMKII inhibition with tatCN19o did not cause such retrograde amnesia that would pose a contraindication for therapy.

neuroscience↗

bioRxiv2021

Extracellular vesicles Transfer Polarized Mitochondria and Increase Cellular Energetics in Ischemic Endothelial Cells

We have demonstrated, for the first time that microvesicles, a sub-type of extracellular vesicles (EVs) derived from hCMEC/D3: a human brain endothelial cell (BEC) line transfer polarized mitochondria to recipient BECs in culture and to neurons in mice acute brain cortical and hippocampal slices. This mitochondrial transfer increased ATP levels by 100 to 200-fold (relative to untreated cells) in the recipient BECs exposed to oxygen-glucose deprivation, an in vitro model of cerebral ischemia. We have also demonstrated that transfer of microvesicles, the larger EV fraction, but not exosomes resulted in increased mitochondrial function in hypoxic endothelial cultures. Gene ontology and pathway enrichment analysis of EVs revealed a very high association to glycolysis-related processes. In comparison to heterotypic macrophage- derived EVs, BEC-derived EVs demonstrated a greater selectivity to transfer mitochondria and increase endothelial cell survival under ischemic conditions. HighlightsO_LIMicrovesicles transfer mitochondria to endothelial cells and brain slice neurons C_LIO_LIMitochondrial transfer increased ATP in ischemic brain endothelial cells (BECs) C_LIO_LITransfer of microvesicles increased mitochondrial function in hypoxic BECs C_LIO_LITransfer of exosomes did not affect mitochondrial function in hypoxic BECs C_LIO_LIHomotypic BEC-derived EVs result in greater ATP levels in the recipient BECs C_LI

bioengineering↗

bioRxiv2018

Cofilin-actin rod formation in neuronal processes after brain ischemia

Functional impairment after brain ischemia results in part from loss of neuronal spines and dendrites, independent of neuronal death. Cofilin-actin rods are covalently linked aggregates of colfilin-1 and actin that form in neuronal processes (neurites) under conditions of ATP depletion and oxidative stress, and which cause neurite degeneration if not disassembled. ATP depletion and oxidative stress occur with differing severity, duration, and time course in different ischemic conditions. Here we evaluated four mouse models of brain ischemia to define the conditions that drive formation of cofilin-actin rods. Three of the models provide early reperfusion: transient middle cerebral artery occlusion (MCAo), transient bilateral common carotid occlusion (CCAo), and cardiac arrest / cardiopulmonary resuscitation (CA/CPR). Early reperfusion restores ATP generating capacity, but also induces oxidative stress. The fourth model, photothrombotic cortical infarction, does not provide reperfusion. Cofilin-actin rods were formed in each of these models, but with differing patterns. Where acute reperfusion occurred, rod formation was maximal within 4 hours after reperfusion. Where infarction occurred, rods continued to form for at least 24 hours after ischemic onset, and extended into the adjacent non-ischemic tissue. Interventions that limit cofilin-actin rod formation may help to preserve integrity of neuronal processes in permanent ischemia.

neuroscience↗