Biology subjects

Engelhardt, A.

Publications and source records attributed to Engelhardt, A..

6 recordsLinked to original sources

bioRxiv2026

Remifentanil self-administration promotes circuit- and sex-specific adaptations within the prefrontal-accumbens pathways

The nucleus accumbens (NAc) and its excitatory input from the medial prefrontal cortex (mPFC) form a critical circuit underlying drug-induced plasticity associated with addiction-related behaviors. However, baseline differences in excitatory signaling across NAc subcircuits and sex-specific neuroadaptations following opioid self-administration remain poorly understood. Here, we examined synaptic signaling in mPFC-NAc pathways in drug-naive mice and after abstinence from remifentanil self-administration. Under drug-naive conditions, AMPA receptor- mediated glutamatergic signaling was generally elevated in D2 medium spiny neurons (MSNs) of both the NAc core and shell across sexes, while females exhibited greater excitatory signaling in D1 MSNs of the NAc core compared with males. Pathway-specific analyses revealed that prelimbic cortex (PL) inputs to NAc core D2 MSNs displayed enhanced calcium-permeable AMPA receptor (CP-AMPAR) signaling and increased presynaptic release relative to D1 MSNs. Following abstinence from remifentanil self-administration, miniature excitatory postsynaptic current analyses showed increased excitatory drive at D1 MSNs and decreased drive at D2 MSNs, largely restricted to the NAc core. At PL-Core D1 MSN synapses, remifentanil reduced AMPA/NMDA ratios, consistent with increased CP-AMPAR incorporation in males and females, while increasing presynaptic signaling exclusively in males. In contrast, PL-Core D2 MSN synapses showed a reduction in presynaptic signaling across sex, while ostensibly weakening postsynaptic signaling selectively in males through reductions in CP-AMPAR signaling. At infralimbic cortex (IL)-shell inputs, a reduction in AMPAR rectification indices at D1 MSN synapses was produced by remifentanil, while release probability was decreased at D2 MSN synapses in males only. Together, these findings reveal sex- and pathway-specific synaptic adaptations within mPFC-NAc circuits that may be obscured by global measures of excitatory transmission and identify baseline circuit differences that may shape opioid-induced plasticity.

neuroscience↗

bioRxiv2023

Adolescent morphine exposure impairs cognitive flexibility in female but not male mice.

Use of prescription opioids continues to rise, especially in adolescent individuals. As adolescence is a critical development window for higher order cognitive functions, thus opioid exposure during this period may have significant long-lasting effects on cognitive function and predisposition individuals to be at greater risk of developing opioid use later in life. Here, we examine previously explored effects of opioid exposure during adolescence on affect-related behavior, motivation, and cognitive flexibility. We find that a two-week exposure to non-contingent morphine during adolescence (i.e., post-weaning) does not alter performance in an elevated plus maze, forced swim test, or motivation for appetitive reward in male or female mice when tested during adolescence or adulthood. Examination of how adolescent morphine impacts cognition revealed impairments in visual-based discriminative learning and cognitive flexibility in female but not male mice, as assessed using an operant-based attentional set-shifting task. Unexpectedly, deficits in discriminative learning are observed when testing occurred during adolescence but not adulthood, whereas impaired performance in the extradimensional shift remained impaired into adulthood. The data indicate that opioid exposure during adolescence has a greater impact on cognitive function in female mice and that these deficits may be more widespread during acute withdrawal periods, while deficits in flexibility more enduring.

neuroscience↗

bioRxiv2020

Intergroup lethal gang attacks do not require fission-fusion dynamics to evolve

Lethal gang attacks, in which multiple aggressors attack a single victim, are among the most widespread forms of violence between human groups. Chimpanzees (Pan troglodytes), as well as wolves (Canis lupus), spotted hyaenas (Crocuta crocuta), and lions (Panthera leo), perform gang attacks during raids. In raids, a few individuals of a group enter another groups territory and attack its members if found in numerical disadvantage. Current theory predicts that raids and gang attacks are linked to fission-fusion dynamics, i.e., the capacity of a group to split into smaller subgroups of variable size and composition. However, over the last decade, research on social mammals without fission-fusion societies nor raiding have shown that they may also be involved in intergroup lethal gang attacks. Thus, neither fission-fusion dynamics nor raiding are required for gang attacks to evolve. Based on our first-ever reports of intergroup gang attacks in the crested macaque (Macaca nigra), combined with the synthesis of earlier observations of such attacks in several species living in stable groups, we develop a new hypothesis about the proximate causes leading to lethal intergroup aggression. We propose that the ability to estimate numerical odds, form coalitionary bonds, and show hostility towards outgroup individuals may suffice to trigger intergroup gang attacks when the conditions favour an imbalance of power between victims and attackers.

animal behavior and cognition↗

bioRxiv2020

The role of parvalbumin interneuron GIRK signaling in regulation of affect and cognition inmale and female mice

Pathological impairments in the regulation of affect (i.e. emotion) and flexible decision-making are commonly observed across numerous neuropsychiatric disorders and are thought to reflect dysfunction of cortical and subcortical circuits that arise in part from imbalances in excitation and inhibition within these structures. Disruptions in GABA transmission, in particular that from parvalbumin-expressing interneurons (PVI), has been highlighted as a likely mechanism by which this imbalance arises, as they regulate excitation and synchronization of principle output neurons. G protein-gated inwardly rectifying potassium ion (GIRK/Kir3) channels are known to modulate excitability and output of pyramidal neurons in areas like the medial prefrontal cortex and hippocampus, however the role GIRK plays in PVI excitability and behavior is unknown. Male and female mice lacking GIRK1 in PVI (Girk1flox/flox:PVcre) and expressing td-tomato in PVI (Girk1flox/flox:PVCre:PVtdtom) exhibited increased open arm time in the elevated plus maze, while males showed an increase in immobile episodes during the forced swim test. Loss of GIRK1 did not alter motivated behavior for an appetitive reward or impair overall performance in an operant-based attention set-shifting model of cognitive flexibility, however it did alter types of errors committed during the visual cue test. Unexpectedly, baseline sex differences were also identified in these tasks, with females exhibiting overall poorer performance compared to males and distinct types of errors, highlighting potential differences in task-related problem solving. Interestingly, reductions in PVI GIRK signaling did not correspond to changes in membrane excitability but did increase action potential firing at higher current injections in PVI of males, but not females. This is the first investigation on the role that PVI GIRK-signaling has on membrane excitability, action potential firing, and their role on affect and cognition together increasing understanding of PVI cellular mechanisms and function.

neuroscience↗

bioRxiv2020

Suppression of pyramidal neuron G protein-gated inwardly rectifying K+ channel signaling impairs prelimbic cortical function and underlies stress-induced deficits in cognitive flexibility

BackgroundImbalance in prefrontal cortical (PFC) pyramidal neuron excitation:inhibition is thought to underlie symptomologies shared across stress-related disorders and neuropsychiatric disease, including dysregulation of emotion and cognitive function. G protein-gated inwardly rectifying K+ (GIRK/Kir3) channels mediate excitability of medial PFC pyramidal neurons, however the functional role of these channels in mPFC-dependent regulation of affect, cognition, and cortical dynamics is unknown. MethodsIn mice harboring a floxed version of the kcnj3 (Girk1) gene, we used a viral-cre approach to disrupt GIRK1-containing channel expression in pyramidal neurons within the prelimbic (PL) or infralimbic (IL) cortices. Additional studies used a novel model of chronic unpredictable stress (CUS) to determine the impact on PL GIRK-dependent signaling and cognitive function. ResultsIn males, loss of pyramidal GIRK-dependent signaling in the PL, but not IL, differentially impacted measures of affect and motivation, and impaired working memory and cognitive flexibility. CUS produced similar deficits in affect and cognition that paralleled a reduction in PL pyramidal GIRK-dependent signaling akin to viral approaches. Viral- and stress-induced behavioral deficits were rescued by systemic injection of a novel, GIRK1-selective agonist, ML-297. Unexpectedly, neither ablation of PL GIRK-dependent signaling or exposure to the CUS regimen impacted affect or cognition in female mice. ConclusionsGIRK-dependent signaling in male mice, but not females, is critical for maintaining optimal PL function and behavioral control. Disruption of this inhibition may underlie stress-related dysfunction of the PL and represent a therapeutic target for treating stress-induced deficits in affect regulation and impaired cognition that reduce quality of life.

neuroscience↗

bioRxiv2019

Sex-specific prefrontal cortex dysfunction underlying opioid-induced cognitive impairment

Women transition to addiction faster and experience greater difficulties remaining abstinent; however, what drives this is unknown. Although poorly understood, loss of cognitive control following chronic drug use has been linked to decreased activation of frontal cortical regions. We show that self-administration of the opioid, remifentanil, causes a long-lasting decrease in ex vivo excitability but augments firing capacity of pyramidal neurons in the prelimbic cortex. This phenomenon occurs faster in females, manifests from sex-specific changes in excitatory and inhibitory synaptic regulation and aligns with impairments in cognitive flexibility. Further, chemogenetic induction of a hypoactive pyramidal neuron state in drug-naive mice produces deficits, while compensating for this hypoactive state protects against cognitive inflexibility resulting from opioid self-administration. These data define cellular and synaptic mechanisms by which opioids impair prefrontal function and cognitive control and indicate that interventions aimed at treating opioid addiction must be tailored based on biological sex.

neuroscience↗