Biology subjects

Scarpa, G.

Publications and source records attributed to Scarpa, G..

5 recordsLinked to original sources

bioRxiv2024

Early life stress influences epilepsy outcomes in mice

Stress is a common seizure trigger that has been implicated in worsening epilepsy outcomes. The neuroendocrine response to stress is mediated by the hypothalamic-pituitary-adrenal (HPA) axis and HPA axis dysfunction worsens epilepsy outcomes, increasing seizure burden, behavioral comorbidities, and risk for sudden unexpected death in epilepsy (SUDEP) in mice. Early life stress (ELS) reprograms the HPA axis into adulthood, impacting both the basal and stress-induced activity. Thus, we propose that ELS may influence epilepsy outcomes by influencing the function of the HPA axis. To test this hypothesis, we utilized the maternal separation paradigm and examined the impact on seizure susceptibility. We show that ELS exerts a sex dependent effect on seizure susceptibility in response to acute administration of the chemoconvulsant, kainic acid, which is associated with an altered relationship between seizure activity and HPA axis function. To further examine the impact of ELS on epilepsy outcomes, we utilized the intrahippocampal kainic acid model of chronic epilepsy in mice previously exposed to maternal separation. We find that the relationship between corticosterone levels and the extent of epileptiform activity is altered in mice subjected to ELS. We demonstrate that ELS impacts behavioral outcomes associated with chronic epilepsy in a sex-dependent manner, with females being more affected. We also observe reduced mortality (presumed SUDEP) in female mice subjected to ELS, consistent with previous findings suggesting a role for HPA axis dysfunction in SUDEP risk. These data demonstrate for the first time that ELS influences epilepsy outcomes and suggest that previous life experiences may impact the trajectory of epilepsy.

neuroscience↗

bioRxiv2024

Sex-dependent effects of early life stress on network and behavioral states.

BackgroundAdverse childhood experiences (ACEs) are associated with numerous detriments in health, including increased vulnerability to psychiatric illnesses. Early life stress (ELS) in rodents has been shown to effectively model several of the behavioral and endocrine impacts of ACEs and has been utilized to investigate the underlying mechanisms contributing to disease. However, the precise neural mechanisms responsible for mediating the impact of ELS on vulnerability to psychiatric illnesses remain largely unknown. MethodsWe use behavior, immunoassay, in vivo LFP recording, histology, and patch clamp to describe the effects of ELS on stress behaviors, endocrinology, network states, protein expression, and cellular physiology in male and female mice. ResultsWe demonstrate that a murine maternal separation (MS) ELS model causes sex-dependent alterations in behavioral and hormonal responses following an acute stressor. Local field potential (LFP) recordings in the basolateral amygdala (BLA) and frontal cortex (FC) reveal similar sex-dependent alterations at baseline, in response to acute ethological stress, and during fear memory extinction, supporting a large body of literature demonstrating that these network states contribute to stress reactivity and vulnerability to psychiatric illnesses. Sex differences were accompanied by altered physiology of BLA principal neurons in males and BLA PV interneurons in females. ConclusionsCollectively, these results implicate novel, sex-dependent mechanisms through which ACEs may impact psychiatric health, involving altered cellular physiology and network states involved in emotional processing.

neuroscience↗

bioRxiv2023

Loss of PV interneurons in the BLA contributes to altered network and behavioral states in chronically epileptic mice

Psychiatric disorders, including anxiety and depression, are highly comorbid in people with epilepsy. However, the mechanisms mediating the shared pathophysiology are currently unknown. There is considerable evidence implicating the basolateral amygdala (BLA) in the network communication of anxiety and fear, a process demonstrated to involve parvalbumin-positive (PV) interneurons. The loss of PV interneurons has been well described in the hippocampus of chronically epileptic mice and in postmortem human tissue of patients with temporal lobe epilepsy (TLE). We hypothesize that a loss of PV interneurons in the BLA may contribute to comorbid mood disorders in epilepsy. To test this hypothesis, we employed a ventral intrahippocampal kainic acid (vIHKA) model of chronic epilepsy in mice, which exhibits profound behavioral deficits associated with chronic epilepsy. We demonstrate a loss of PV interneurons and dysfunction of remaining PV interneurons in the BLA of chronically epileptic mice. Further, we demonstrate altered principal neuron function and impaired coordination of BLA network and behavioral states in chronically epileptic mice. To determine whether these altered network and behavioral states were due to the loss of PV interneurons, we ablated a similar percentage of PV interneurons observed in chronically epileptic mice by stereotaxically injecting AAV-Flex-DTA into the BLA of PV-Cre mice. Loss of PV interneurons in the BLA is sufficient to alter behavioral states, inducing deficits in fear learning and recall of fear memories. These data suggest that compromised inhibition in the BLA in chronically epileptic mice contributes to behavioral deficits, suggesting a novel mechanism contributing to comorbid anxiety and epilepsy. Significance StatementPsychiatric illnesses and epilepsy are highly comorbid and negatively impact the quality of life of people with epilepsy. The pathophysiological mechanisms mediating the bidirectional relationship between mood disorders and epilepsy remain unknown and, therefore, treatment options remain inadequate. Here we demonstrate a novel mechanism, involving the loss of PV interneurons in the BLA, leading to a corruption of network and behavioral states in mice. These findings pinpoint a critical node and demonstrate a novel cellular and circuit mechanism involved in the comorbidity of psychiatric illnesses and epilepsy.

neuroscience↗

bioRxiv2023

Early life stress impairs VTA coordination of BLA network and behavioral states

Motivated behaviors, such as social interactions, are governed by the interplay between mesocorticolimbic structures, such as the ventral tegmental area (VTA), basolateral amygdala (BLA), and medial prefrontal cortex (mPFC). Adverse childhood experiences and early life stress (ELS) can impact these networks and behaviors, which is associated with increased risk for psychiatric illnesses. While it is known that the VTA projects to both the BLA and mPFC, the influence of these inputs on local network activity which govern behavioral states - and whether ELS impacts VTA-mediated network communication - remains unknown. Our study demonstrates that VTA inputs influence BLA oscillations and mPFC activity, and that ELS weakens the ability of the VTA to coordinate BLA network states, likely due to ELS-induced impairments in dopamine signaling between the VTA and BLA. Consequently, ELS mice exhibit increased social avoidance, which can be recapitulated in control mice by inhibiting VTA-BLA communication. These data suggest that ELS impacts social reward via the VTA-BLA dopamine network.

neuroscience↗

bioRxiv2020

Genetically-identified cell types in avian pallium mirror core principles of excitatory and inhibitory neurons in mammalian cortex

In vertebrates, advanced cognitive abilities are associated with a highly developed telencephalic pallium. In mammals, the six-layered neocortex of the pallium is composed of excitatory neurons and inhibitory interneurons, organized across layers into microcircuits. These organizational principles are proposed to support efficient, high-level information processing. Comparative perspectives across vertebrates provide a lens to understand what common features of pallium are important for complex cognition. For non-mammalian vertebrates that exhibit complex cognitive abilities, such as birds, the physiology of identified pallial cell types and their circuit organization are largely unresolved. Using viral tools to target excitatory vs. inhibitory neurons in the zebra finch auditory association pallium, we systematically tested predictions derived from mammalian neocortex. We identify two segregated neuronal populations that exhibit profound physiological and computational similarities with mammalian excitatory and inhibitory neocortical cells. Specifically, despite dissimilarities in gross architecture, avian association pallium exhibits neocortex-typical coding principles, and inhibitory-dependent cortical synchrony, gamma oscillations, and local suppression. Our findings suggest parallel evolution of physiological and network roles for pallial cell types in amniotes with substantially divergent pallial organization.

neuroscience↗