Biology subjects

Hearing, M.

Publications and source records attributed to Hearing, M..

7 recordsLinked to original sources

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↗

bioRxiv2023

Protracted morphine withdrawal corresponds with sex-specific alterations to motivated behavior and mesoaccumbal subcircuit dopamine cell plasticity

BackgroundOpioid use disorder is associated with enduring psychological withdrawal symptoms believed to contribute to drug abuse. Amongst these are shifts in motivational states, wherein pursuit of drug consumption exceeds that of non-drug rewards, reinforcing escalated opioid use and relapse vulnerability. A critical regulator of behavioral reinforcement, the mesoaccumbal dopamine (DA) system is thought to be both necessary and sufficient for opioid motivation. However, previous research into its involvement in opioid withdrawal has been limited to acute vs protracted timepoints, global neuroadaptations vs those in subcircuits, and overwhelmingly focused on males vs females. MethodsEvaluations of effort-based motivated behavior for both sucrose and morphine reward were combined with patch clamp electrophysiological assessments of synaptic plasticity within lateral vs medial DA neurons projecting to the lateral vs medial nucleus accumbens shell during protracted morphine withdrawal in male and female mice. Further effects of mesoaccumbal subcircuit inhibition on motivated behavior for sucrose were also measured. ResultsProtracted morphine withdrawal was found to be associated with elevations in morphine seeking, intake, and motivation compared to saline controls in both sexes. Escalation of intake was paralleled by a male-exclusive reduction in motivation for the non-drug reward, sucrose. Male-exclusive neuroadaptations during protracted withdrawal were also found, with reductions in neuronal excitability and increased inhibitory (GABAAR-dependent) synaptic transmission found in lateral ventral tegmental area (VTA) DA neurons projecting to the lateral nucleus accumbens shell, though not in medial DA projections to the medial shell. Finally, chemogenetic inhibition of the lateral but not medial subcircuit was found to significantly reduce motivated responding for sucrose in male morphine-naive mice. ConclusionsThese data suggest that protracted opioid withdrawal is associated with a sex-independent increase in opioid consumption and motivation. They also suggest that male-specific reductions in motivation for non-drug reward during protracted withdrawal may be driven by a hypoactive state in a lateral mesoaccumbal DA subcircuit driven in part by increased inhibition of DA cells. These insights may be useful in development of therapies that temper withdrawal-associated psychological states predisposed towards prolonged and escalated opioid intake, a major treatment goal for OUD patients.

neuroscience↗

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↗

bioRxiv2019

Cell-type and region-specific nucleus accumbens AMPAR plasticity associated with morphine reward, reinstatement, and spontaneous withdrawal

Despite evidence that morphine-related pathologies reflect adaptations in NAc glutamate signaling, substantial gaps in basic information remain. The current study examines the impact of non-contingent acute, repeated, and withdrawal-inducing morphine dosing regimens on glutamate transmission in D1- or D2-MSNs in the NAcSh and NAcC sub-regions in hopes of identifying excitatory plasticity that may contribute to differing facets of opioid addiction-related behavior. Three hours following an acute morphine injection (10 mg/kg), average miniature excitatory postsynaptic current (mEPSC) amplitude mediated by AMPA-type glutamate receptors was increased at D1-MSNs in the both the shell and core regions, whereas only the frequency of events was elevated at D2-MSNs in the shell. In contrast, somatic withdrawal induced by escalating dose of repeated morphine twice per day (20, 40, 60, 80, 100mg/kg) only enhanced mEPSC frequency at D2-MSNs in the shell 24 hrs following the final drug exposure. Further, drug re-exposure 10-14 days following a preference-inducing regimen of morphine produced a rapid and enduring endocytosis of GluA2-containing AMPARs at D1-MSNs in the shell, that when blocked by an intra-NAc shell infusion of the Tat-GluA23Y peptide, increased reinstatement of morphine place preference - a phenomenon distinctly different than effects previously found with cocaine. The present study is the first to directly identify unique circuit specific adaptations in NAc glutamate synaptic transmission associated with morphine-related acute reward and somatic withdrawal as well as post-abstinence short-term plasticity. While differing classes of abused drugs (i.e., psychostimulants and opioids) produce seemingly similar bidirectional plasticity in the NAc following exposure to relapse-linked stimuli, our findings indicate this plasticity has distinct behavioral consequences.\n\nCompliance with Ethical StandardsThe authors have no conflicts of interest to disclose. All authors have given their consent for manuscript submission. The research in the current study used mice single- or group-housed on a 12 h light/dark cycle with food and water available ad libitum with experiments run during the light portion. All experiments were approved by the University of Minnesota and Marquette University Institutional Animal Care and Use Committee. The following funding sources made the study possible: National Institute for Neurological Disorders and Stroke (P30 NS062158); National Institute on Drug Abuse grant K99 DA038706 (to M.H.), R00DA038706 (M.H.), R00DA038706-04S1 (A.C.M), R01DA019666 (M.J.T.), K02DA035459 (M.J.T.) and T32 DA007234 (A.E.I.).

neuroscience↗

bioRxiv2019

Chronic unpredictable stress promotes cell-specific plasticity in prefrontal cortex D1 and D2 pyramidal neurons

Exposure to unpredictable environmental stress is widely recognized as a major determinant for risk and severity in neuropsychiatric disorders such as major depressive disorder, anxiety, schizophrenia, and PTSD. The ability of ostensibly unrelated disorders to give rise to seemingly similar psychiatric phenotypes highlights a need to identify circuit-level concepts that could unify diverse factors under a common pathophysiology. Although difficult to disentangle a causative effect of stress from other factors on medial prefrontal cortex (PFC) dysfunction, a wealth of data from humans and rodents demonstrates that the PFC is a key target of stress. The present study sought to identify a model of chronic unpredictable stress (CUS) which induces affective behaviors in C57BL6J mice and once established, measure spike firing and the ability to evoke an action potential in mPFC layer 5/6 pyramidal neurons. Adult male mice received 2 weeks of less intense stress or 2 or 4 weeks of more intense CUS followed by sucrose preference for assessment of anhedonia, elevated plus maze for assessment of anxiety and forced swim test for assessment of depressive-like behaviors. Our findings indicate that more intense CUS exposure results in increased anhedonia, anxiety, and depressive behaviors, while the less intense stress results in no measured behavioral phenotypes. Once a behavioral model was established, mice were euthanized approximately 21 days post-stress for whole-cell patch clamp recordings from layer 5/6 pyramidal neurons in the prelimbic (PrL) and infralimbic (IL) cortices. No significant differences were initially observed in intrinsic cell excitability in either region. However, post-hoc analysis and subsequent confirmation using transgenic mice expressing tdtomato or eGFP under control of dopamine D1- or D2-type receptor showed that D1-expressing pyramidal neurons (D1-PYR) in the PrL exhibit reduced thresholds to fire an action potential (increased excitability) but impaired firing capacity at more depolarized potentials, whereas D2-expressing pyramidal neurons showed an overall reduction in excitability and spike firing frequency. Examination of synaptic transmission showed that D1- and D2-PYR in exhibit differences in basal excitatory and inhibitory signaling under naive conditions. In CUS mice, D1-PYR showed increased frequency of both miniature excitatory and inhibitory postsynaptic currents, whereas D2-PYR only showed a reduction in excitatory currents. These findings demonstrate that the intrinsic physiology and synaptic regulation of D1- and D2-PYR subpopulations differentially undergo stress-induced plasticity that may have functional implications for stress-related pathology, and that these adaptations may reflect unique differences in basal properties regulating output of these cells.

neuroscience↗