Vinay Parikh

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Papers by Vinay Parikh

Paternal nicotine enhances fear memory, reduces nicotine administration, and alters hippocampal genetic and neural function in offspring

Addiction Biology, 2019

Nicotine use remains highly prevalent with tobacco and e‐cigarette products consumed worldwide. H... more Nicotine use remains highly prevalent with tobacco and e‐cigarette products consumed worldwide. However, increasing evidence of transgenerational epigenetic inheritance suggests that nicotine use may alter behavior and neurobiology in subsequent generations. We tested the effects of chronic paternal nicotine exposure in C57BL6/J mice on fear conditioning in F1 and F2 offspring, as well as conditioned fear extinction and spontaneous recovery, nicotine self‐administration, hippocampal cholinergic functioning, RNA expression, and DNA methylation in F1 offspring. Paternal nicotine exposure was associated with enhanced contextual and cued fear conditioning and spontaneous recovery of extinguished fear memories. Further, nicotine reinforcement was reduced in nicotine‐sired mice, as assessed in a self‐administration paradigm. These behavioral phenotypes were coupled with altered response to nicotine, upregulated hippocampal nicotinic acetylcholine receptor binding, reduced evoked hippocamp...

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Glutamate receptor interacting protein acts within the prefrontal cortex to blunt cocaine seeking

Neuropharmacology, 2019

Glutamate receptor interacting protein (GRIP) is a neuronal scaffolding protein that anchors GluA... more Glutamate receptor interacting protein (GRIP) is a neuronal scaffolding protein that anchors GluA2-containing AMPA receptors to the cell membrane. GRIP plays a critical role in activity-dependent synaptic plasticity, including that which occurs after drug exposure. Given that cocaine administration alters glutamate receptor trafficking within the prefrontal cortex (PFC), a better understanding of the role of receptor trafficking proteins could lead to a more complete understanding of addictive phenotypes. AMPA receptor trafficking in general, and GRIP specifically, is known to play a role in cocaine seeking and conditioned reward in the nucleus accumbens, but its role in the PFC has not been characterized. The current study demonstrates that conditional deletion of GRIP1 in the medial prefrontal cortex increases the motivation for cocaine and potentiates cue-induced reinstatement of cocaine seeking in male and female mice. As no effects of PFC GRIP1 deletion were seen in reinstatement of food seeking, strategy set-shifting, or reversal learning the effects on cocaine seeking are not related to generalized alterations in cognitive function. While disrupting GRIP1 might be expected to lead to decreased AMPA transmission, our electrophysiological data indicate an increase in sEPSC amplitude in the prefrontal cortex and a corresponding decrease in paired pulse facilitation in the nucleus accumbens. Taken together this suggests a strengthening of the PFC to NAc input following prefrontal GRIP1 deletion that may mediate the enhanced drug seeking behavior.

Septohippocampal cholinergic system at the intersection of stress and cognition: Current trends and translational implications

European Journal of Neuroscience

Neuro-immune modulation of cholinergic signaling in an addiction vulnerability trait

bioRxiv (Cold Spring Harbor Laboratory), Dec 5, 2022

Running title: Ubiquitination and cytokines in addiction Author contributions: HC determined the ... more Running title: Ubiquitination and cytokines in addiction Author contributions: HC determined the rats' phenotype and measured cytokine levels in brain and spleen, determined the effects of LPS on cytokine concentrations, and prepared brain tissues for measurement of choline transporter concentrations and modifications. ECH and VP determined subcellular choline transporter concentrations, ubiquitinylation levels, and the effects of LPS. VP, NCT and MS designed the experiments. NCT and MS wrote the original draft of the paper. All authors contributed to the statistical analyses of the data and to the editing of the final manuscript.

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Stress Regulation of Sustained Attention and the Cholinergic Attention System

Biological Psychiatry, 2020

Background: Stress exacerbates symptoms of schizophrenia and attention deficit hyperactivity diso... more Background: Stress exacerbates symptoms of schizophrenia and attention deficit hyperactivity disorder, which are characterized by impairments in sustained attention. Yet how stress regulates attention remains largely unexplored. Here we investigated whether a 6-day variable stressor (VS) altered sustained attention and the cholinergic attention system in male and female rats. Methods: Sustained attention was tested with the sustained attention task (SAT). Successful performance on SAT relies on the release of acetylcholine (ACh) into the cortex from cholinergic neurons in the nucleus basalis of Meynert (NBM). Thus, we evaluated whether VS altered the morphology of these neurons with a novel approach using a Cre-dependent virus in genetically modified ChAT::Cre rats, a species used for this manipulation only. Next, electrochemical recordings measured cortical ACh following VS. Finally, we used RNAseq to identify VS-induced transcriptional changes in the NBM. Results: VS impaired attentional performance in SAT and increased the dendritic complexity of NBM cholinergic neurons in both sexes. NBM cholinergic neurons are mainly under inhibitory control, so this morphological change could increase inhibition on these neurons, reducing downstream ACh release to impair attention. Indeed, VS decreased ACh release in the prefrontal cortex of males. Quantification of global transcriptional changes revealed that, although VS induced many sex-specific changes in gene expression, it increased several signaling molecules in both sexes.

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Nicotine Withdrawal and Deficits in Cognitive Flexibility: Possible Ties to Aberrations in Frontostriatal BDNF Signaling

Nicotine addiction continues to be a leading cause of preventable death worldwide. Despite the pl... more Nicotine addiction continues to be a leading cause of preventable death worldwide. Despite the plethora of available treatments for smoking cessation, smoking relapse after attempts to quit remains high. It is possible that impairments in cognitive flexibility and underlying neurochemical circuits in nicotine addicts may foster maladaptive behaviors that affect individuals' ability to refrain from taking drugs. Here we characterized the effects of spontaneous nicotine withdrawal on cognitive flexibility in mice using an operant strategy set-shifting task. Because frontostriatal circuits are critical for cognitive flexibility and brain-derived neurotrophic factor (BDNF) modulates glutamate plasticity, we also explored the effects of nicotine withdrawal on these neurochemical substrates. Adult male C57BL/6J mice were trained in an operant task that required the animals to switch from using a spatial response-driven strategy to a visual cue-based strategy to achieve rewards. Mice w...

Neuro-immune modulation of cholinergic signaling in an addiction vulnerability trait

Sign-tracking (ST) describes the propensity to approach and contact a Pavlovian reward cue. By co... more Sign-tracking (ST) describes the propensity to approach and contact a Pavlovian reward cue. By contrast, goal-trackers (GTs) respond to such a cue by retrieving the reward. These behaviors index the presence of opponent cognitive-motivational traits, with STs exhibiting attentional control deficits, behavior dominated by incentive motivational processes, and vulnerability for addictive drug taking. Attentional control deficits in STs were previously attributed to attenuated cholinergic signaling, resulting from deficient translocation of intracellular choline transporters (CHTs) into synaptosomal plasma membrane. Here we investigated a post-translational modification of CHTs – poly-ubiquitination - and tested the hypothesis that elevated cytokine signaling in STs contributes to CHT modification. We demonstrated that intracellular CHTs, but not plasma membrane CHTs, are highly ubiquitinated in male and female sign-tracking rats when compared with GTs. Moreover, levels of cytokines me...

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Nicotine Dependence in Schizophrenia: Contributions of Nicotinic Acetylcholine Receptors

Neuroscience of Nicotine

Abstract The prevalence of tobacco smoking in subjects with schizophrenia is strikingly higher th... more Abstract The prevalence of tobacco smoking in subjects with schizophrenia is strikingly higher than the normal population. Nicotine, a psychoactive ingredient of tobacco, induces diverse behavioral effects by activating nicotinic acetylcholine receptors (nAChRs) and influencing chemical transmission and downstream cellular targets in the central nervous system. Substantial evidence from the preclinical and clinical studies indicates that nAChRs are dysregulated in schizophrenia. People diagnosed with schizophrenia experience a combination of positive, negative, and cognitive symptoms, and nicotine intake may represent a strategy to remediate these symptoms by normalizing nAChR deficit. However, the highly addictive properties of nicotine limit its use as a drug candidate. Therefore, efforts to develop chemical ligands that target specific nAChRs in the brain represent a viable therapeutic option to effectively manage the symptoms of schizophrenia.

The forebrain cholinergic system and age-related decline in and compensation of attentional capacities

Aging is characterized by an increase in inter-individual variability in cognitive capacity. Slig... more Aging is characterized by an increase in inter-individual variability in cognitive capacity. Slight decrements in learning and memory emerge; however, age-related shifts in attentional function remain controversial. In pathological aging, however, attentional dysfunction is prominent and the circuitry critical to signal detection and thus attention as a whole, the corticopetal cholinergic system, exhibits substantial disruption and deterioration. One contributing factor to cholinergic dysfunction is the loss of neurotrophic support, specifically nerve growth factor's high-affinity receptor tropomyosin-related kinase A (trkA). Previous cross-sectional studies demonstrated that reduced trkA receptor levels selectively impaired attentional capacity in aged rats. However, it remains unclear if reduced trkA receptors in the basal forebrain (BF) interact with aging to elicit these attentional deficits. Thus developmental suppression of trkA receptors on attentional capacity and BF cho...

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Corticotropin releasing factor in the nucleus basalis of Meynert impairs attentional performance and reduces levels of glutamate and taurine in male and female rats

Neuropharmacology

a Model Of Cognitive Dysfunction: Constrained Demands On Cholinergic Transmission And Attentional Capacities In Cht + /− Mice : Op03-06

Prospects for Neurotrophic Factor-Based Early Intervention in Schizophrenia: Lessons Learned from the Effects of Antipsychotic Drugs on Cognition, Neurogenesis, and Neurotrophic Factors

CNS & neurological disorders drug targets, 2022

Although reducing psychotic symptoms in schizophrenia has been a major focus of therapeutic inter... more Although reducing psychotic symptoms in schizophrenia has been a major focus of therapeutic interventions for decades, improving cognition is considered a better predictor of functional outcome. However, the most commonly prescribed antipsychotic drugs (APDs) show only marginal beneficial effects on cognition in patients with schizophrenia. The neural mechanisms underlying cognitive disturbances in schizophrenia remain unknown that makes drug development efforts very challenging. Since neurotrophic factors are the primary architects of neurogenesis, synaptic plasticity, learning and memory, the findings from preclinical and clinical studies that assess changes in neurogenesis and neurotrophic factors and their relationship to cognitive performance in schizophrenia, and how these mechanisms might be impacted by APD treatment, may provide valuable clues in developing therapies to combat cognitive deficit in schizophrenia. Numerous evidence produced over the years suggests deficit in a...

Exosomes in Age-Related Cognitive Decline: Mechanistic Insights and Improving Outcomes

Frontiers in Aging Neuroscience

Aging is the most prominent risk factor for cognitive decline, yet behavioral symptomology and un... more Aging is the most prominent risk factor for cognitive decline, yet behavioral symptomology and underlying neurobiology can vary between individuals. Certain individuals exhibit significant age-related cognitive impairments, while others maintain intact cognitive functioning with only minimal decline. Recent developments in genomic, proteomic, and functional imaging approaches have provided insights into the molecular and cellular substrates of cognitive decline in age-related neuropathologies. Despite the emergence of novel tools, accurately and reliably predicting longitudinal cognitive trajectories and improving functional outcomes for the elderly remains a major challenge. One promising approach has been the use of exosomes, a subgroup of extracellular vesicles that regulate intercellular communication and are easily accessible compared to other approaches. In the current review, we highlight recent findings which illustrate how the analysis of exosomes can improve our understand...

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Disrupted choline clearance and sustained acetylcholine release in vivo by a common choline transporter coding variant associated with poor attentional control in humans

Transport of choline via the neuronal high-affinity choline transporter (CHT; SLC5A7) is essentia... more Transport of choline via the neuronal high-affinity choline transporter (CHT; SLC5A7) is essential for cholinergic terminals to synthesize and release acetylcholine (ACh). In humans, we previously demonstrated an association between a common CHT coding substitution (rs1013940; Ile89Val) and reduced attentional control as well as attenuated frontal cortex activation. Here, we used a CRISPR/Cas9 approach to generate mice expressing the I89V substitution and assessed, in vivo, CHT-mediated choline transport, and ACh release. Relative to wild type (WT) mice, CHT-mediated clearance of choline in mice expressing one or two Val89 alleles was reduced by over 80% cortex and by over 50% in striatum. Choline clearance in CHT Val89 mice was further reduced by neuronal inactivation. Deficits in ACh release, 5 and 10 min after repeated depolarization at a low, behaviorally relevant frequency, support an attenuated reloading capacity of cholinergic neurons in mutant mice. The density of CHTs in to...

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Dynamic interplay of frontoparietal cholinergic innervation and cortical reorganization in the regulation of attentional capacities in aging

Cortical remodeling is linked to age-related cognitive changes in humans; however, the mechanisms... more Cortical remodeling is linked to age-related cognitive changes in humans; however, the mechanisms underlying cortical reorganization in aging remain unknown. Here we examined the consequences of mild cholinergic thinning of the prefrontal cortex (PFC) and parietal cortex (PC) on attention performance-associated changes in cortical activity in young and aged rats. Prefrontal manipulation produced attentional deficits in aged but not young rats regardless of cholinergic pruning. Stereological assessment of c-fos expression revealed age-related reductions in occipital activity and a corresponding increase in PC activity, but these patterns did not correlate with performance. PC cholinergic deafferentation produced opposite changes in PFC recruitment between young and aged rats. Cholinergic pruning reversed the effects of PFC/PC cholinergic manipulations on the activity of CaMKII- and GAD-positive neurons in aged rats. Our results indicate that cortical shifts depend on multiple factors...

Developmental suppression of forebrain trkA receptors and attentional capacities in aging rats: A longitudinal study

Behavioural Brain Research, 2017

Basal forebrain (BF) cholinergic neurons innervating the cortex regulate cognitive, specifically ... more Basal forebrain (BF) cholinergic neurons innervating the cortex regulate cognitive, specifically attentional, processes. Cholinergic atrophy and cognitive decline occur at an accelerated pace in age-related neurodegenerative disorders such as Alzheimer's disease; however, the mechanism responsible for this phenomenon remains unknown. Here we hypothesized that developmental suppression of nerve growth factor signaling, mediated via tropomyosin-related kinase A (trkA) receptors, would escalate age-related attentional vulnerability. An adeno-associated viral vector expressing trkA shRNA (AAV-trkA) was utilized to knockdown trkA receptors in postnatal rats at an ontogenetic time point when cortical cholinergic inputs mature, and the impact of this manipulation on performance was assessed in animals maintained on an operant attention task throughout adulthood and until old (24 months) age. A within-subject comparison across different time points illustrated a gradual age-related decline in attentional capacities. However, the performance under baseline and distracted conditions did not differ between the AAV-trkA-infused and animals infused with a vector expressing shRNA against the control protein luciferase at any time point. Additional analysis of cholinergic measures conducted at 24 months showed that the capacity of cholinergic terminals to release acetylcholine following a depolarizing stimulus, cortical cholinergic fiber density and BF cholinergic cell size remained comparable between the two groups. Contrary to our predictions, these data indicate that developmental BF trkA disruption does not impact age-related changes in attentional functions. It is possible that life-long engagement in cognitive activity might have potentially rescued the developmental insults on the cholinergic system, thus preserving attentional capacities in advanced age.

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Cognitive control deficits during mecamylamine-precipitated withdrawal in mice: Possible links to frontostriatal BDNF imbalance

Neurobiology of Learning and Memory, 2016

Nicotine is a major psychoactive and addictive component of tobacco. Although cessation of tobacc... more Nicotine is a major psychoactive and addictive component of tobacco. Although cessation of tobacco use produces various somatic and affective symptoms, withdrawal-related cognitive deficits are considered to be a critical symptom that predict relapse. Therefore, delineating the cognitive mechanisms of nicotine withdrawal may likely provide gainful insights into the neurobiology of nicotine addiction. The present study was designed to examine the effects of nicotine withdrawal induced by mecamylamine, a non-specific nicotinic receptor (nAChR) antagonist, on cognitive control processes in mice using an operant strategy switching task. Brainderived neurotrophic factor (BDNF) modulates synaptic transmission in frontostriatal circuits, and these circuits are critical for executive functions. Thus, we examined the effects of mecamylamine-precipitated nicotine withdrawal on prefrontal and striatal BDNF protein expression. Mice undergoing precipitated nicotine withdrawal required more trials to attain strategy switching criterion as compared to the controls. Error analysis indicated that impaired performance in these animals was mostly related to their inability to execute the new strategy. The striatal/prefrontal BDNF ratios robustly increased following precipitated nicotine withdrawal. Moreover, higher BDNF ratios were associated with longer task acquisition. Collectively, our findings illustrate that mecamylamine-induced nicotine withdrawal disrupts cognitive control processes and that these changes are possibly linked to perturbations in frontostriatal BDNF signaling.

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nAChR dysfunction as a common substrate for schizophrenia and comorbid nicotine addiction: Current trends and perspectives

Schizophrenia Research, 2016

Introduction-The prevalence of tobacco use in the population with schizophrenia is enormously hig... more Introduction-The prevalence of tobacco use in the population with schizophrenia is enormously high. Moreover, nicotine dependence is found to be associated with symptom severity and poor outcome in patients with schizophrenia. The neurobiological mechanisms that explain schizophrenia-nicotine dependence comorbidity are not known. This study systematically reviews the evidence highlighting the contribution of nicotinic acetylcholine receptors (nAChRs) to nicotine abuse in schizophrenia. Methods-Electronic data bases (Medline, Google Scholar, and Web of Science) were searched using the selected key words that match the aims set forth for this review. A total of 275 articles were used for the qualitative synthesis of this review. Results-Substantial evidence from preclinical and clinical studies indicated that dysregulation of α7 and β2-subunit containing nAChRs account for the cognitive and affective symptoms of schizophrenia and nicotine use may represent a strategy to remediate these symptoms. Additionally, recent meta-analyses proposed that early tobacco use may itself increase the risk of developing schizophrenia. Genetic studies demonstrating that nAChR dysfunction that may act as a shared vulnerability factor for comorbid tobacco dependence and schizophrenia were found to support this view. The development of nAChR modulators was considered an effective therapeutic strategy to ameliorate psychiatric symptoms and to promote smoking cessation in schizophrenia patients. Conclusions-The relationship between schizophrenia and smoking is complex. While the debate for the self-medication versus addiction vulnerability hypothesis continues, it is widely accepted that a dysfunction in the central nAChRs represent a common substrate for various symptoms of schizophrenia and comorbid nicotine dependence.

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Chemogenetic inhibition of prefrontal projection neurons constrains top-down control of attention in young but not aged rats

The prefrontal cortex (PFC) governs top-down control of attention and is known to be vulnerable i... more The prefrontal cortex (PFC) governs top-down control of attention and is known to be vulnerable in aging. Cortical reorganization with increased PFC recruitment is suggested to account for functional compensation. Here, we hypothesized that reduced PFC output would exert differential effects on attentional capacities in young and aged rats, with the latter exhibiting a more robust decline in performance. A chemogenetic approach involving designer receptors exclusively activated by designer drugs was utilized to determine the impact of silencing PFC projection neurons in rats performing an operant attention task. Visual distractors were presented in all behavioral testing sessions to tax attentional resources. Under control conditions, aged rats exhibited impairments in discriminating signals with the shortest duration from non-signal events. Surprisingly, chemogenetic inhibition of PFC output neurons did not worsen performance amongst aged animals. Conversely, significant impairment...

Neuromodulation of BAG co-chaperones by HIV-1 viral proteins and H2O2: implications for HIV-associated neurological disorders

Despite increasing numbers of aged individuals living with HIV, the mechanisms underlying HIV-ass... more Despite increasing numbers of aged individuals living with HIV, the mechanisms underlying HIV-associated neurological disorders (HANDs) remain elusive. As HIV-1 pathogenesis and aging are characterized by oxidative stress as well as altered protein quality control (PQC), reactive oxygen species (ROS) themselves might constitute a molecular mediator of neuronal PQC by modulating BCL-2 associated athanogene (BAG) family members. Present results reveal H 2 O 2 replicated and exacerbated a reduction in neuronal BAG3 induced by the expression of HIV-1 viral proteins (i.e., Tat and Nef), while also causing an upregulation of BAG1. Such a reciprocal regulation of BAG3 and BAG1 levels was also indicated in two animal models of HIV, the doxycycline-inducible Tat (iTat) and the Tg26 mouse. Inhibiting oxidative stress via antioxidants in primary culture was capable of partially preserving neuronal BAG3 levels as well as electrophysiological functioning otherwise altered by HIV-1 viral proteins...

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