Publications by authors named "David M Lovinger"

160 Publications

Corticostriatal Circuit Models of Cognitive Impairments Induced by Fetal Exposure to Alcohol.

Biol Psychiatry 2021 Oct 21;90(8):516-528. Epub 2021 May 21.

National Institute on Alcohol Abuse and Alcoholism, Intramural Research Program, National Institutes of Health, Bethesda, Maryland. Electronic address:

The term fetal alcohol spectrum disorder includes a group of diseases caused by fetal alcohol exposure (FAE). Patients with fetal alcohol spectrum disorder display heterogeneous socioemotional and cognitive deficits, particularly in the domain of executive function, that share symptoms with other neuropsychiatric disorders. Despite the availability of several preclinical models, the developmental brain defects causally linked to behavioral deficits induced by FAE remain poorly understood. Here, we first review the effects of FAE on corticostriatal development and its impact on both corticostriatal pathway function and cognitive abilities. We propose three non-mutually exclusive circuit models of corticostriatal dysfunctions to account for some of the FAE-induced cognitive deficits. One model posits that associative-sensorimotor imbalance causes hyper goal-directed behavior, and a second model implies that alteration of prefrontal-striatal behavioral suppression circuits results in loss of behavioral inhibition. A third model suggests that local striatal circuit deficits affect striatal neuronal ensemble function to impair action selection and performance. Finally, we discuss how preclinical approaches applied to these circuit models could offer potential rescue strategies for executive function deficits in patients with fetal alcohol spectrum disorder.
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http://dx.doi.org/10.1016/j.biopsych.2021.05.014DOI Listing
October 2021

Control of exploration, motor coordination and amphetamine sensitization by cannabinoid CB receptors expressed in medium spiny neurons.

Eur J Neurosci 2021 08 13;54(3):4934-4952. Epub 2021 Jul 13.

Department of Pharmacology, University of Washington School of Medicine, Seattle, WA, USA.

Activation of cannabinoid 1 receptors (CB R) modulates multiple behaviours, including exploration, motor coordination and response to psychostimulants. It is known that CB R expressed by either excitatory or inhibitory neurons mediates different behavioural responses to CB R activation, yet the involvement of CB R expressed by medium spiny neurons (MSNs), the neuronal subpopulation that expresses the highest level of CB R in the CNS, remains unknown. We report a new genetically modified mouse line that expresses functional CB R in MSN on a CB R knockout (KO) background (CB R mice). The absence of cannabimimetic responses measured in CB R KO mice was not rescued in CB R mice, nor was decreased spontaneous locomotion, impaired instrumental behaviour or reduced amphetamine-triggered hyperlocomotion measured in CB R KO mice. Significantly, reduced novel environment exploration of an open field and absence of amphetamine sensitization (AS) measured in CB R KO mice were fully rescued in CB R mice. Impaired motor coordination in CB R KO mice measured on the Rotarod was partially rescued in CB R mice. Thus, CB R expressed by MSN control exploration, motor coordination, and AS. Our study demonstrates a new functional roles for cell specific CB R expression and their causal link in the control of specific behaviors.
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http://dx.doi.org/10.1111/ejn.15381DOI Listing
August 2021

Spinal astrocyte aldehyde dehydrogenase-2 mediates ethanol metabolism and analgesia in mice.

Br J Anaesth 2021 08 29;127(2):296-309. Epub 2021 Apr 29.

Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA. Electronic address:

Background: Little is known about the targets in the CNS that mediate ethanol analgesia. This study explores the role of spinal astrocyte aldehyde dehydrogenase-2 (ALDH2), a key ethanol-metabolising enzyme, in the analgesic effects of ethanol in mice.

Methods: Astrocyte and hepatocyte ALHD2-deficient mice were generated and tested in acute and chronic pain models. Cell-type-specific distribution of ALDH2 was analysed by RNA in situ hybridisation in spinal slices from astrocytic ALDH2-deficient mice and their wild-type littermates. Spinal ethanol metabolites and γ-aminobutyric acid (GABA) content were measured using gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry.

Results: ALDH2 mRNA was expressed in both astrocytes and neurones in spinal cord slices. Astrocyte ALDH2-deficient mice had decreased expression of ALDH2 mRNA in astrocytes, but not in neurones. Astrocyte ALDH2 deficiency inhibited ethanol-derived acetate, but not acetaldehyde content in spinal cord tissues. Depletion of spinal astrocyte ALDH2 selectively inhibited ethanol-induced anti-nociceptive effect, but not the effect of ethanol, on motor function. Astrocyte ALDH2 deficiency abolished ethanol-induced GABA elevation. The ethanol metabolite acetate produced anti-nociception and increased GABA synthesis in a manner similar to ethanol. I.T. delivery of either GABA or GABA receptor antagonists prevented ethanol and acetate-induced analgesia.

Conclusions: These findings provide evidence that ALDH2 in spinal astrocytes mediates spinal ethanol metabolism and ethanol-induced analgesic effects by promoting GABA synthesis and GABAergic transmission in spinal cord.
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http://dx.doi.org/10.1016/j.bja.2021.02.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362281PMC
August 2021

Cannabis use, abuse, and withdrawal: Cannabinergic mechanisms, clinical, and preclinical findings.

J Neurochem 2021 06 16;157(5):1674-1696. Epub 2021 May 16.

Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, Center on Compulsive Behaviors, National Institutes of Health, Bethesda, MD, USA.

Cannabis sativa is the most widely used illicit drug in the world. Its main psychoactive component is delta-9-tetrahydrocannabinol (THC), one of over 100 phytocannabinoid compounds produced by the cannabis plant. THC is the primary compound that drives cannabis abuse potential and is also used and prescribed medically for therapeutic qualities. Despite its therapeutic potential, a significant subpopulation of frequent cannabis or THC users will develop a drug use syndrome termed cannabis use disorder. Individuals suffering from cannabis use disorder exhibit many of the hallmarks of classical addictions including cravings, tolerance, and withdrawal symptoms. Currently, there are no efficacious treatments for cannabis use disorder or withdrawal symptoms. This makes both clinical and preclinical research on the neurobiological mechanisms of these syndromes ever more pertinent. Indeed, basic research using animal models has provided valuable evidence of the neural molecular and cellular actions of cannabis that mediate its behavioral effects. One of the main components being central action on the cannabinoid type-one receptor and downstream intracellular signaling related to the endogenous cannabinoid system. Back-translational studies have provided insight linking preclinical basic and behavioral biology research to better understand symptoms observed at the clinical level. This narrative review aims to summarize major research elucidating the molecular, cellular, and behavioral manifestations of cannabis/THC use that play a role in cannabis use disorder and withdrawal.
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http://dx.doi.org/10.1111/jnc.15369DOI Listing
June 2021

Brain ethanol metabolism by astrocytic ALDH2 drives the behavioural effects of ethanol intoxication.

Nat Metab 2021 03 22;3(3):337-351. Epub 2021 Mar 22.

Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.

Alcohol is among the most widely used psychoactive substances worldwide. Ethanol metabolites such as acetate, thought to be primarily the result of ethanol breakdown by hepatic aldehyde dehydrogenase 2 (ALDH2), contribute to alcohol's behavioural effects and alcoholism. Here, we show that ALDH2 is expressed in astrocytes in the mouse cerebellum and that ethanol metabolism by astrocytic ALDH2 mediates behavioural effects associated with ethanol intoxication. We show that ALDH2 is expressed in astrocytes in specific brain regions and that astrocytic, but not hepatocytic, ALDH2 is required to produce ethanol-derived acetate in the mouse cerebellum. Cerebellar astrocytic ALDH2 mediates low-dose ethanol-induced elevation of GABA levels, enhancement of tonic inhibition and impairment of balance and coordination skills. Thus, astrocytic ALDH2 controls the production, cellular and behavioural effects of alcohol metabolites in a brain-region-specific manner. Our data indicate that astrocytic ALDH2 is an important, but previously under-recognized, target in the brain to alter alcohol pharmacokinetics and potentially treat alcohol use disorder.
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http://dx.doi.org/10.1038/s42255-021-00357-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294184PMC
March 2021

Long-term alcohol consumption alters dorsal striatal dopamine release and regulation by D2 dopamine receptors in rhesus macaques.

Neuropsychopharmacology 2021 07 15;46(8):1432-1441. Epub 2021 Jan 15.

Laboratory for Integrative Neuroscience, Division of Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA.

The dorsal striatum (DS) is implicated in behavioral and neural processes including action control and reinforcement. Alcohol alters these processes in rodents, and it is believed that the development of alcohol use disorder involves changes in DS dopamine signaling. In nonhuman primates, the DS can be divided into caudate and putamen subregions. As part of a collaborative effort examining the effects of long-term alcohol self-administration in rhesus macaques, we examined DS dopamine signaling using fast-scan cyclic voltammetry. We found that chronic alcohol self-administration resulted in several dopamine system adaptations. Most notably, dopamine release was altered in a sex- and region-dependent manner. Following long-term alcohol consumption, male macaques, regardless of abstinence status, had reduced dopamine release in putamen, while only male macaques in abstinence had reduced dopamine release in caudate. In contrast, female macaques had enhanced dopamine release in the caudate, but not putamen. Dopamine uptake was also enhanced in females, but not males (regardless of abstinence state). We also found that dopamine D2/3 autoreceptor function was reduced in male, but not female, alcohol drinkers relative to control groups. Finally, we found that blockade of nicotinic acetylcholine receptors inhibited evoked dopamine release in nonhuman primates. Altogether, our findings demonstrate that long-term alcohol consumption can sex-dependently alter dopamine release, as well as its feedback control mechanisms in both DS subregions.
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http://dx.doi.org/10.1038/s41386-020-00938-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209056PMC
July 2021

Ethanol induces persistent potentiation of 5-HT receptor-stimulated GABA release at synapses on rat hippocampal CA1 neurons.

Neuropharmacology 2021 02 1;184:108415. Epub 2020 Dec 1.

Section on Synaptic Pharmacology, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA. Electronic address:

Several studies have shown that ethanol (EtOH) can enhance the activity of GABAergic synapses via presynaptic mechanisms, including in hippocampal CA1 neurons. The serotonin type 3 receptor (5-HT-R) has been implicated in the neural actions of ethanol (EtOH) and in modulation of GABA release from presynaptic terminals. In the present study, we investigated EtOH modulation of GABA release induced by 5-HT-R activation using the mechanically isolated neuron/bouton preparation from the rat CA1 hippocampal subregion. EtOH application before and during exposure to the selective 5-HT receptor agonist, m-chlorophenylbiguanide (mCPBG) potentiated the mCPBG-induced increases in the peak frequency and charge transfer of spontaneous GABAergic inhibitory postsynaptic currents. Interestingly, the potentiation was maintained even after EtOH was removed from the preparation. A protein kinase A inhibitor reduced the magnitude of EtOH potentiation. Fluorescent Ca imaging showed that Ca transients in the presynaptic terminals increased during EtOH exposure. These findings indicate that EtOH produces long-lasting potentiation of 5-HT-induced GABA release by modulating calcium levels, via a process involving cAMP-mediated signaling in presynaptic terminals.
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http://dx.doi.org/10.1016/j.neuropharm.2020.108415DOI Listing
February 2021

A Circuit-Based Information Approach to Substance Abuse Research.

Trends Neurosci 2021 02 6;44(2):122-135. Epub 2020 Nov 6.

Department of Psychology, University of California, San Diego, La Jolla, CA, USA.

Recent animal research on substance-use disorders (SUDs) has emphasized learning models and the identification of 'addiction-prone' animals. Meanwhile, basic neuroscientific research has elucidated molecular, cellular, and circuit functions with increasing sophistication. However, SUD-related research is hampered by continued arguments over which animal models are more 'addiction like', as well as the facile assignment of behaviors to a given brain region and vice versa. We argue that SUD-related research would benefit from a 'bottom-up' approach including: (i) the characterization of different brain circuits to understand their normal function as well as how they respond to drugs and contribute to SUDs; and (ii) a focus on the use patterns and neurobiological effects of different substances to understand the range of critical SUD-related in vivo phenotypes.
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http://dx.doi.org/10.1016/j.tins.2020.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856012PMC
February 2021

Wake up and smell the dopamine: new mechanisms mediating dopamine activity fluctuations related to sleep and psychostimulant sensitivity.

Neuropsychopharmacology 2021 03 6;46(4):683-684. Epub 2020 Nov 6.

Laboratory for Integrative Neuroscience, Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, 20892, USA.

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http://dx.doi.org/10.1038/s41386-020-00903-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027680PMC
March 2021

Reinforcing actions through the thalamostriatal circuit.

Neuropsychopharmacology 2021 01;46(1):245-246

Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, US National Institutes of Health, Rockville, 20852, MD, USA.

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http://dx.doi.org/10.1038/s41386-020-00814-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688928PMC
January 2021

Dopamine D2 receptor signaling on iMSNs is required for initiation and vigor of learned actions.

Neuropsychopharmacology 2020 11 18;45(12):2087-2097. Epub 2020 Aug 18.

Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD, 20852, USA.

Striatal dopamine D2 receptors (D2Rs) are important for motor output. Selective deletion of D2Rs from indirect pathway-projecting medium spiny neurons (iMSNs) impairs locomotor activities in a task-specific manner. However, the role of D2Rs in the initiation of motor actions in reward seeking and taking is not fully understood, and there is little information about how receptors contribute under different task demands and with different outcome types. The iMSN-D2Rs modulate neuronal activity and synaptic transmission, exerting control on circuit functions that may play distinct roles in action learning and performance. Selective deletion of D2Rs on iMSNs resulted in slower action initiation and response rate in an instrumental conditioning task, but only when performance demand was increased. The iMSN-Drd2KO mice were also slower to initiate swimming in a T-maze procedural learning task but were unimpaired in cognitive function and behavioral flexibility. In contrast, in a Pavlovian discrimination learning task, iMSN-Drd2KO mice exhibited normal acquisition and extinction of rewarded responding. The iMSN-Drd2KO mice showed performance deficits at all phases of rotarod skill learning. These findings reveal that dopamine modulation through iMSN-D2Rs influences the ability to self-initiate actions, as well as the willingness and/or vigor with which these responses are performed. However, these receptors seem to have little influence on simple associative learning or on stimulus-driven responding. The loss of normal D2R roles may contribute to disorders in which impaired dopamine signaling leads to hypokinesia or impaired initiation of specific voluntary actions.
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http://dx.doi.org/10.1038/s41386-020-00799-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547091PMC
November 2020

Cannabinoids, Endocannabinoids and Sleep.

Front Mol Neurosci 2020 22;13:125. Epub 2020 Jul 22.

Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institute of Health (NIH), Bethesda, MD, United States.

Sleep is a vital function of the nervous system that contributes to brain and bodily homeostasis, energy levels, cognitive ability, and other key functions of a variety of organisms. Dysfunctional sleep induces neural problems and is a key part of almost all human psychiatric disorders including substance abuse disorders. The hypnotic effects of cannabis have long been known and there is increasing use of phytocannabinoids and other formulations as sleep aids. Thus, it is crucial to gain a better understanding of the neurobiological basis of cannabis drug effects on sleep, as well as the role of the endogenous cannabinoid system in sleep physiology. In this review article, we summarize the current state of knowledge concerning sleep-related endogenous cannabinoid function derived from research on humans and rodent models. We also review information on acute and chronic cannabinoid drug effects on sleep in these organisms, and molecular mechanisms that may contribute to these effects. We point out the potential benefits of acute cannabinoids for sleep improvement, but also the potential sleep-disruptive effects of withdrawal following chronic cannabinoid drug use. Prescriptions for future research in this burgeoning field are also provided.
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http://dx.doi.org/10.3389/fnmol.2020.00125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388834PMC
July 2020

Stress and behavioral correlates in the head-fixed method: stress measurements, habituation dynamics, locomotion, and motor-skill learning in mice.

Sci Rep 2020 07 22;10(1):12245. Epub 2020 Jul 22.

Section on Synaptic Pharmacology and In Vivo Neural Function, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, US National Institutes of Health, Rockville, MD, 20852, USA.

Manual restriction of head movement, or head-fixation, of awake rodents allows for sophisticated investigation of neural circuits in vivo, that would otherwise be impossible in completely freely moving animals. While it is known that head-fixation induces stress, the scale of this stress and habituation dynamics remain unclear. We used the Mobile HomeCage system (Neurotar Ltd, Finland) where animals have their heads fixed to an aluminum frame but are otherwise freely moving in an ultralight carbon container floating above an air-dispensing base. For 25 consecutive days, mice were head-fixed while standing on the air-lifted platform for 2 h per day and blood samples were taken periodically to measure variation in the stress-related hormone, corticosterone. We showed that the initial increase in corticosterone concentration is followed by a return to control level throughout the days of head-fixed training. We also found a locomotor correlate of this drop. We conducted a battery of stress-sensitive behavioral paradigms in freely-moving mice that revealed minor differences following chronic head-fixation. Finally, we analyzed motor-skill learning in the head-fixed setup with a floating container. We believe that our results may contribute to better interpretation of past literature and future in vivo experiments using head-fixed animals.
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http://dx.doi.org/10.1038/s41598-020-69132-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376196PMC
July 2020

Gestational alcohol exposure disrupts cognitive function and striatal circuits in adult offspring.

Nat Commun 2020 05 22;11(1):2555. Epub 2020 May 22.

Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Bethesda, MD, 20892, USA.

Fetal alcohol exposure (FAE) is the leading preventable developmental cause of cognitive dysfunction. Even in the absence of binge drinking, alcohol consumption during pregnancy can leave offspring deficient. However, the mechanisms underlying these deficiencies are unknown. Using a mouse model of gestational ethanol exposure (GEE), we show increased instrumental lever-pressing and disruption of efficient habitual actions in adults, indicative of disrupted cognitive function. In vivo electrophysiology reveals disrupted action encoding in dorsolateral striatum (DLS) associated with altered habit learning. GEE mice exhibit decreased GABAergic transmission onto DLS projection neurons, including inputs from parvalbumin interneurons, and increased endocannabinoid tone. Chemogenetic activation of DLS parvalbumin interneurons reduces the elevated lever pressing of GEE mice. Pharmacologically increasing endocannabinoid tone mimics GEE effects on cognition and synaptic transmission. These findings show GEE induces long-lasting deficits in cognitive function that may contribute to human FAE, and identify potential mechanisms for future therapeutic targeting.
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http://dx.doi.org/10.1038/s41467-020-16385-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244532PMC
May 2020

Allosteric modulation of metabotropic glutamate receptors in alcohol use disorder: Insights from preclinical investigations.

Adv Pharmacol 2020 2;88:193-232. Epub 2020 Mar 2.

Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, US National Institutes of Health, Rockville, MD, United States.

Metabotropic glutamate (mGlu) receptors are family C G protein-coupled receptors (GPCRs) that modulate neuronal excitability and synaptic transmission throughout the nervous system. Owing to recent advances in development of subtype-selective allosteric modulators of mGlu receptors, individual members of the mGlu receptor family have been proposed as targets for treating a variety of neurological and psychiatric disorders, including substance use disorders. In this chapter, we highlight preclinical evidence that allosteric modulators of mGlu receptors could be useful for reducing alcohol consumption and preventing relapse in alcohol use disorder (AUD). We begin with an overview of the preclinical models that are used to study mGlu receptor involvement in alcohol-related behaviors. Alcohol exposure causes adaptations in both expression and function of various mGlu receptor subtypes, and pharmacotherapies aimed at reversing these adaptations have the potential to reduce alcohol consumption and seeking. Positive allosteric modulators (PAMs) of mGlu and negative allosteric modulators of mGlu show particular promise for reducing alcohol intake and/or preventing relapse. Finally, this chapter discusses important considerations for translating preclinical findings toward the development of clinically useful drugs, including the potential for PAMs to avoid tolerance issues that are frequently observed with repeated administration of GPCR agonists.
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http://dx.doi.org/10.1016/bs.apha.2020.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384598PMC
September 2020

Alcohol effects on globus pallidus connectivity: Role of impulsivity and binge drinking.

PLoS One 2020 26;15(3):e0224906. Epub 2020 Mar 26.

Clinical NeuroImaging Research Core, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, United States of America.

Despite the harm caused by binge drinking, the neural mechanisms leading to risky and disinhibited intoxication-related behaviors are not well understood. Evidence suggests that the globus pallidus externus (GPe), a substructure within the basal ganglia, participates in inhibitory control processes, as examined in stop-signaling tasks. In fact, studies in rodents have revealed that alcohol can change GPe activity by decreasing neuronal firing rates, suggesting that the GPe may have a central role in explaining impulsive behaviors and failures of inhibition that occur during binge drinking. In this study, twenty-five healthy volunteers underwent intravenous alcohol infusion to achieve a blood alcohol level of 0.08 g/dl, which is equivalent to a binge drinking episode. A resting state functional magnetic resonance imaging scan was collected prior to the infusion and at binge-level exposure. Functional connectivity analysis was used to investigate the association between alcohol-induced changes in GPe connectivity, drinking behaviors, and impulsivity traits. We found that individuals with greater number of drinks or heavy drinking days in the recent past had greater alcohol-induced deficits in GPe connectivity, particularly to the striatum. Our data also indicated an association between impulsivity and alcohol-induced deficits in GPe-frontal/precentral connectivity. Moreover, alcohol induced changes in GPe-amygdala circuitry suggested greater vulnerabilities to stress-related drinking in some individuals. Taken together, these findings suggest that alcohol may interact with impulsive personality traits and drinking patterns to drive alterations in GPe circuitry associated with behavioral inhibition, possibly indicating a neural mechanism by which binge drinking could lead to impulsive behaviors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224906PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098584PMC
May 2020

Prenatal alcohol exposure in the second trimester-equivalent increases the seizure susceptibility in developing rats.

Alcohol 2020 06 28;85:153-164. Epub 2020 Feb 28.

Georgetown University Medical Center, Department of Pediatrics, Washington, DC, USA. Electronic address:

We have previously reported that prenatal alcohol exposure (PAE) in the 2nd trimester-equivalent of gestation is associated with increased N-methyl-d-aspartate (NMDA)-induced generalized tonic-clonic seizures (GTCSs) prevalence in postpartum developing rats. Whether the 1st trimester-equivalent of gestation is also a vulnerable period for developing GTCSs following PAE is unknown. Here, we investigated the effects of a single episode of PAE at embryonic day 8 (E8, in the 1st trimester-equivalent) or E18 (in the 2nd trimester-equivalent) on NMDA-induced seizures in developing rats at postnatal day 7 (P7, the equivalent of preterm newborns) and P15 (the equivalent of term infants). Pregnant Sprague-Dawley rats were given a single oral dose of ethanol (5 g/kg body weight) at E8 or E18 and the postpartum rats were tested for the susceptibility to NMDA-induced seizures at either P7 or P15. NMDA-induced seizures consisted of wild running-like behavior (WRLB), flexion seizures (FSs), clonic seizures (CSs), GTCSs, and tonic seizures (TSs); these seizures were observed in both control-treated and PAE-treated, male and female, P7 and P15 rats. Quantification reveals that the overall prevalence of CSs, GTCSs and TSs occurrence were significantly increased in the E18-PAE group compared to E8-PAE group, adjusting for sex and postnatal day. Furthermore, the overall prevalence of FSs and TSs occurrence was significantly increased in PAE-treated males compared to females, adjusting for embryonic stage and postnatal day. The overall prevalence of WRLB and FSs occurrence was also increased in PAE-P7 rats compared to PAE-P15 rats, adjusting for sex and embryonic stage. We conclude that the susceptibility to develop GTCSs was higher when PAE occurred in the 2nd rather than in the 1st trimester-equivalent of gestation.
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http://dx.doi.org/10.1016/j.alcohol.2020.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340347PMC
June 2020

Operant self-stimulation of thalamic terminals in the dorsomedial striatum is constrained by metabotropic glutamate receptor 2.

Neuropsychopharmacology 2020 08 29;45(9):1454-1462. Epub 2020 Jan 29.

Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, US National Institutes of Health, Rockville, MD, 20852, USA.

Dorsal striatal manipulations including stimulation of dopamine release and activation of medium spiny neurons (MSNs) are sufficient to drive reinforcement-based learning. Glutamatergic innervation of the striatum by the cortex and thalamus is a critical determinant of MSN activity and local regulation of dopamine release. However, the relationship between striatal glutamatergic afferents and behavioral reinforcement is not well understood. We evaluated the reinforcing properties of optogenetic stimulation of thalamostriatal terminals, which are associated with vesicular glutamate transporter 2 (Vglut2) expression, in the dorsomedial striatum (DMS), a region implicated in goal-directed behaviors. In mice expressing channelrhodopsin-2 (ChR2) under control of the Vglut2 promoter, optical stimulation of the DMS reinforced operant lever-pressing behavior. Mice also acquired operant self-stimulation of thalamostriatal terminals when ChR2 expression was virally targeted to the intralaminar thalamus. Stimulation trains that supported operant responding evoked dopamine release in the DMS and excitatory postsynaptic currents in DMS MSNs. Our previous work demonstrated that the presynaptic G protein-coupled receptor metabotropic glutamate receptor 2 (mGlu) robustly inhibits glutamate and dopamine release induced by activation of thalamostriatal afferents. Thus, we examined the regulation of thalamostriatal self-stimulation by mGlu. Administration of an mGlu agonist or an mGlu-selective positive allosteric modulator reduced self-stimulation. Conversely, blockade of these receptors increased thalamostriatal self-stimulation, suggesting that endogenous activation of these receptors negatively modulates the reinforcing properties of thalamostriatal activity. These findings demonstrate that stimulation of thalamic terminals in the DMS is sufficient to reinforce a self-initiated action, and that thalamostriatal reinforcement is constrained by mGlu activation.
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http://dx.doi.org/10.1038/s41386-020-0626-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360544PMC
August 2020

Dose-dependent alcohol effects on electroencephalogram: Sedation/anesthesia is qualitatively distinct from sleep.

Neuropharmacology 2020 03 14;164:107913. Epub 2019 Dec 14.

Laboratory for Integrative Neuroscience, Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA. Electronic address:

Alcohol is commonly used as a sleep inducer/aid by humans. However, individuals diagnosed with alcohol use disorders have sleep problems. Few studies have examined the effect of ethanol on physiological features of sedation and anesthesia, particularly at high doses. This study used polysomnography and a rapid, unbiased scoring of vigilance states with an automated algorithm to provide a thorough characterization of dose-dependent acute ethanol effects on sleep and electroencephalogram (EEG) power spectra in C57BL/6J male mice. Ethanol had a narrow dose-response effect on sleep. Only a high dose (4.0 g/kg) produced a unique, transient state that could not be characterized in terms of canonical sleep-wake states, so we dubbed this novel state Drug-Induced State with a Characteristic Oscillation in the Theta Band (DISCO-T). After this anesthetic effect, the high dose of alcohol promoted NREM sleep by increasing the duration of NREM bouts while reducing wake. REM sleep was differentially responsive to the circadian timing of ethanol administration. EEG power spectra proved more sensitive to ethanol than sleep measures as there were clear effects of ethanol at 2.0 and 4.0 g/kg doses. Ethanol promoted delta oscillations and suppressed faster frequencies, but there were clear, differential effects on wake and REM EEG power based on the timing of the ethanol injection. Understanding the neural basis of the extreme soporific effects of high dose ethanol may aid in treating acute toxicity brought about by patterns of excessive binge consumption commonly observed in young people.
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http://dx.doi.org/10.1016/j.neuropharm.2019.107913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678031PMC
March 2020

Age-dependent impairment of metabotropic glutamate receptor 2-dependent long-term depression in the mouse striatum by chronic ethanol exposure.

Alcohol 2020 02 21;82:11-21. Epub 2019 Jun 21.

Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, US National Institutes of Health, 5625 Fishers Lane TS-13, Rockville, MD, 20892, USA. Electronic address:

Chronic alcohol exposure is associated with increased reliance on behavioral strategies involving the dorsolateral striatum (DLS), including habitual or stimulus-response behaviors. Presynaptic G protein-coupled receptors (GPCRs) on cortical and thalamic inputs to the DLS inhibit glutamate release, and alcohol-induced disruption of presynaptic GPCR function represents a mechanism by which alcohol could disinhibit DLS neurons and thus bias toward use of DLS-dependent behaviors. Metabotropic glutamate receptor 2 (mGlu) is a G-coupled GPCR that robustly modulates glutamate transmission in the DLS, inducing long-term depression (LTD) at both cortical and thalamic synapses. Loss of mGlu function has recently been associated with increased ethanol seeking and consumption, but the ability of alcohol to produce adaptations in mGlu function in the DLS has not been investigated. We exposed male C57Bl/6J mice to a 2-week chronic intermittent ethanol (CIE) paradigm followed by a brief withdrawal period, then used whole-cell patch clamp recordings of glutamatergic transmission in the striatum to assess CIE effects on mGlu-mediated synaptic plasticity. We report that CIE differentially disrupts mGlu-mediated long-term depression in the DLS vs. dorsomedial striatum (DMS). Interestingly, CIE-induced impairment of mGlu-LTD in the dorsolateral striatum is only observed when alcohol exposure occurs during adolescence. Incubation of striatal slices from CIE-exposed adolescent mice with a positive allosteric modulator of mGlu fully rescues mGlu-LTD. In contrast to the 2-week CIE paradigm, acute exposure of striatal slices to ethanol concentrations that mimic ethanol levels during CIE exposure fails to disrupt mGlu-LTD. We did not observe a reduction of mGlu mRNA or protein levels following CIE exposure, suggesting that alcohol effects on mGlu occur at the functional level. Our findings contribute to growing evidence that adolescents are uniquely vulnerable to certain alcohol-induced neuroadaptations, and identify enhancement of mGlu activity as a strategy to reverse the effects of adolescent alcohol exposure on DLS physiology.
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http://dx.doi.org/10.1016/j.alcohol.2019.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925350PMC
February 2020

Unbalanced calcium channel activity underlies selective vulnerability of nigrostriatal dopaminergic terminals in Parkinsonian mice.

Sci Rep 2019 03 19;9(1):4857. Epub 2019 Mar 19.

Transgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.

Dopamine (DA) release in striatum is functionally segregated across a dorsolateral/ventromedial axis. Interestingly, nigrostriatal DA signaling disruption in Parkinson's disease (PD) preferentially affects the dorsolateral striatum. The relationship between afferent presynaptic calcium transients (PreCaTs) in DA terminals and DA release in dorsolateral (Caudato-Putamen, DLS) and ventromedial (Nucleus Accumbens Shell, VS) striatal subregions was examined by ex vivo real-time dual-recording in conditional transgenic mice expressing the calcium indicator protein GCaMP3. In DLS, minimal increases in cytosolic calcium trigger steep DA release while PreCaTs and DA release in VS both were proportional to the number of pulses in burst stimulation. Co-expressing α-synuclein with the Parkinson's disease (PD)-associated A53T mutation and GCaMP3 in midbrain DA neurons revealed augmented cytosolic steady state and activity-dependent intra-terminal calcium levels preferentially in DLS, as well as hyperactivation and enhanced expression of N-type calcium channels. Thus, unbalanced calcium channel activity is a presynaptic mechanism to consider in the multifaceted pathogenic pathways of progressive neurodegeneration.
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http://dx.doi.org/10.1038/s41598-019-41091-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425036PMC
March 2019

Influence of nonsynaptic α1 glycine receptors on ethanol consumption and place preference.

Addict Biol 2020 03 18;25(2):e12726. Epub 2019 Mar 18.

Laboratory of Neurophysiology, Department of Physiology, Universidad de Concepcion, Concepcion, Chile.

Here, we used knock-in (KI) mice that have ethanol-insensitive alpha 1 glycine receptors (GlyRs) (KK385/386AA) to examine how alpha 1 GlyRs might affect binge drinking and conditioned place preference. Data show that tonic alpha 1 GlyR-mediated currents were exclusively sensitive to ethanol only in wild-type mice. Behavioral studies showed that the KI mice have a higher intake of ethanol upon first exposure to drinking and greater conditioned place preference to ethanol. This study suggests that nonsynaptic alpha 1-containing GlyRs have a role in motivational and early reinforcing effects of ethanol.
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http://dx.doi.org/10.1111/adb.12726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751026PMC
March 2020

Correction to: Presynaptic Ethanol Actions: Potential Roles in Ethanol Seeking.

Authors:
David M Lovinger

Handb Exp Pharmacol 2018 ;248:617

Laboratory for Integrative Neuroscience, Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.

The Acknowledgements unfortunately went missing to be included in the chapter.
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http://dx.doi.org/10.1007/164_2018_189DOI Listing
January 2018

Active Zone Proteins RIM1αβ Are Required for Normal Corticostriatal Transmission and Action Control.

J Neurosci 2019 02 17;39(8):1457-1470. Epub 2018 Dec 17.

Section on Synaptic Pharmacology & In Vivo Neural Function, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland 20852, and

Dynamic regulation of synaptic transmission at cortical inputs to the dorsal striatum is considered critical for flexible and efficient action learning and control. Presynaptic mechanisms governing the properties and plasticity of glutamate release from these inputs are not fully understood, and the corticostriatal synaptic processes that support normal action learning and control remain unclear. Here we show in male and female mice that conditional deletion of presynaptic proteins RIM1αβ (RIM1) from excitatory cortical neurons impairs corticostriatal synaptic transmission in the dorsolateral striatum. Key forms of presynaptic G-protein-coupled receptor-mediated short- and long-term striatal plasticity are spared following RIM1 deletion. Conditional RIM1 KO mice show heightened novelty-induced locomotion and impaired motor learning on the accelerating rotarod. They further show heightened self-paced instrumental responding for food and impaired learning of a habitual instrumental response strategy. Together, these findings reveal a selective role for presynaptic RIM1 in neurotransmitter release at prominent basal ganglia synapses, and provide evidence that RIM1-dependent processes help to promote the refinement of skilled actions, constrain goal-directed behaviors, and support the learning and use of habits. Our daily functioning hinges on the ability to flexibly and efficiently learn and control our actions. How the brain encodes these capacities is unclear. Here we identified a selective role for presynaptic proteins RIM1αβ in controlling glutamate release from cortical inputs to the dorsolateral striatum, a brain structure critical for action learning and control. Behavioral analysis of mice with restricted genetic deletion of RIM1αβ further revealed roles for RIM1αβ-dependent processes in the learning and refinement of motor skills and the balanced expression of goal-directed and habitual actions.
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http://dx.doi.org/10.1523/JNEUROSCI.1940-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381247PMC
February 2019

Contributions of nucleus accumbens dopamine to cognitive flexibility.

Eur J Neurosci 2019 08 10;50(3):2023-2035. Epub 2018 Oct 10.

Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.

There is a compelling evidence that midbrain dopamine (DA) neurons and their projections to the ventral striatum provide a mechanism for motivating reward-seeking behavior, and for utilizing information about unexpected reward prediction errors (RPEs) to guide behavior based on current, rather than historical, outcomes. When this mechanism is compromised in addictions, it may produce patterns of maladaptive behavior that remain obdurate in the face of contrary information and even adverse consequences. Nonetheless, DAergic contributions to performance on behavioral tasks that rely on the ability to flexibly update stimulus-reward relationships remains incompletly understood. In the current study, we used a discrimination and reversal paradigm to monitor subsecond DA release in mouse NAc core (NAc) using in vivo fast-scan cyclic voltammetry (FSCV). We observed post-choice elevations in phasic NAc DA release; however, increased DA transients were only evident during early reversal when mice made responses at the newly rewarded stimulus. Based on this finding, we used in vivo optogenetic (eNpHR) photosilencing and (Channelrhodopsin2 [ChR2]) photostimulation to assess the effects of manipulating VTA-DAergic fibers in the NAc on reversal performance. Photosilencing the VTA → NAc DAergic pathway during early reversal increased errors, while photostimulation did not demonstrably affect behavior. Taken together, these data provide additional evidence of the importance of NAc DA release as a neural substrate supporting adjustments in learned behavior after a switch in expected stimulus-reward contingencies. These findings have possible implications for furthering understanding the role of DA in persistent, maladaptive decision-making characterizing addictions.
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http://dx.doi.org/10.1111/ejn.14152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6421566PMC
August 2019

Dual Dopaminergic Regulation of Corticostriatal Plasticity by Cholinergic Interneurons and Indirect Pathway Medium Spiny Neurons.

Cell Rep 2018 09;24(11):2883-2893

Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Rockville, MD 20852, USA. Electronic address:

Endocannabinoid (eCB)-mediated long-term depression (LTD) requires dopamine (DA) D2 receptors (D2Rs) for eCB mobilization. The cellular locus of the D2Rs involved in LTD induction remains highly debated. We directly examined the role in LTD induction of D2Rs expressed by striatal cholinergic interneurons (Chls) and indirect pathway medium spiny neurons (iMSNs) using neuron-specific targeted deletion of D2Rs. Deletion of Chl-D2Rs (Chl-Drd2KO) impaired LTD induction in both subtypes of MSNs. LTD induction was restored in the Chl-Drd2KO mice by an M1-selective muscarinic acetylcholine receptor antagonist. In contrast, after the deletion of iMSN-D2Rs (iMSN-Drd2KO), LTD induction was intact in MSNs. Separate interrogation of direct pathway and iMSNs revealed a deficit in LTD induction only at synapses onto iMSNs that lack D2Rs. LTD induction in iMSNs was restored by D2R agonist application. Our findings suggest that Chl D2Rs strongly modulate LTD induction in MSNs, with iMSN-D2Rs having a weaker, iMSN-specific, modulatory effect.
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http://dx.doi.org/10.1016/j.celrep.2018.08.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182771PMC
September 2018

Synaptic plasticity mechanisms common to learning and alcohol use disorder.

Learn Mem 2018 09 16;25(9):425-434. Epub 2018 Aug 16.

Laboratory for Integrative Neuroscience, Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892, USA.

Alcohol use disorders include drinking problems that span a range from binge drinking to alcohol abuse and dependence. Plastic changes in synaptic efficacy, such as long-term depression and long-term potentiation are widely recognized as mechanisms involved in learning and memory, responses to drugs of abuse, and addiction. In this review, we focus on the effects of chronic ethanol (EtOH) exposure on the induction of synaptic plasticity in different brain regions. We also review findings indicating that synaptic plasticity occurs in vivo during EtOH exposure, with a focus on ex vivo electrophysiological indices of plasticity. Evidence for effects of EtOH-induced or altered synaptic plasticity on learning and memory and EtOH-related behaviors is also reviewed. As this review indicates, there is much work needed to provide more information about the molecular, cellular, circuit, and behavioral consequences of EtOH interactions with synaptic plasticity mechanisms.
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http://dx.doi.org/10.1101/lm.046722.117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097767PMC
September 2018

Parameter Optimization Using Covariance Matrix Adaptation-Evolutionary Strategy (CMA-ES), an Approach to Investigate Differences in Channel Properties Between Neuron Subtypes.

Front Neuroinform 2018 31;12:47. Epub 2018 Jul 31.

Krasnow Institute of Advanced Study, George Mason University, Fairfax, VA, United States.

Computational models in neuroscience can be used to predict causal relationships between biological mechanisms in neurons and networks, such as the effect of blocking an ion channel or synaptic connection on neuron activity. Since developing a biophysically realistic, single neuron model is exceedingly difficult, software has been developed for automatically adjusting parameters of computational neuronal models. The ideal optimization software should work with commonly used neural simulation software; thus, we present software which works with models specified in declarative format for the MOOSE simulator. Experimental data can be specified using one of two different file formats. The fitness function is customizable as a weighted combination of feature differences. The optimization itself uses the covariance matrix adaptation-evolutionary strategy, because it is robust in the face of local fluctuations of the fitness function, and deals well with a high-dimensional and discontinuous fitness landscape. We demonstrate the versatility of the software by creating several model examples of each of four types of neurons (two subtypes of spiny projection neurons and two subtypes of globus pallidus neurons) by tuning to current clamp data. Optimizations reached convergence within 1,600-4,000 model evaluations (200-500 generations × population size of 8). Analysis of the parameters of the best fitting models revealed differences between neuron subtypes, which are consistent with prior experimental results. Overall our results suggest that this easy-to-use, automatic approach for finding neuron channel parameters may be applied to current clamp recordings from neurons exhibiting different biochemical markers to help characterize ionic differences between other neuron subtypes.
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http://dx.doi.org/10.3389/fninf.2018.00047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079282PMC
July 2018

Presence of Inhibitory Glycinergic Transmission in Medium Spiny Neurons in the Nucleus Accumbens.

Front Mol Neurosci 2018 11;11:228. Epub 2018 Jul 11.

Laboratory of Neurophysiology, Department of Physiology, Universidad de Concepción, Concepción, Chile.

It is believed that the rewarding actions of drugs are mediated by dysregulation of the mesolimbic dopaminergic system leading to increased levels of dopamine in the nucleus accumbens (nAc). It is widely recognized that GABAergic transmission is critical for neuronal inhibition within nAc. However, it is currently unknown if medium spiny neurons (MSNs) also receive inhibition by means of glycinergic synaptic inputs. We used a combination of proteomic and electrophysiology studies to characterize the presence of glycinergic input into MSNs from nAc demonstrating the presence of glycine transmission into nAc. In D1 MSNs, we found low frequency glycinergic miniature inhibitory postsynaptic currents (mIPSCs) which were blocked by 1 μM strychnine (STN), insensitive to low (10, 50 mM) and high (100 mM) ethanol (EtOH) concentrations, but sensitive to 30 μM propofol. Optogenetic experiments confirmed the existence of STN-sensitive glycinergic IPSCs and suggest a contribution of GABA and glycine neurotransmitters to the IPSCs in nAc. The study reveals the presence of glycinergic transmission in a non-spinal region and opens the possibility of a novel mechanism for the regulation of the reward pathway.
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http://dx.doi.org/10.3389/fnmol.2018.00228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050475PMC
July 2018

Classification of GABAergic neuron subtypes from the globus pallidus using wild-type and transgenic mice.

J Physiol 2018 09 30;596(17):4219-4235. Epub 2018 Jul 30.

Laboratory for Integrative Neuroscience, Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.

Key Points: Classifying different subtypes of neurons in deep brain structures is a challenge and is crucial to better understand brain function. Understanding the diversity of neurons in the globus pallidus (GP), a brain region positioned to influence afferent and efferent information processing within basal ganglia, could help to explain a variety of brain functions. We present a classification of neurons from the GP using electrophysiological data from wild-type mice and confirmation using transgenic mice. This work will help researchers to identify specific neuronal subsets in the GP of wild-type mice when transgenic mice with labelled neurons are lacking.

Abstract: Classification of the extensive neuronal diversity in the brain is fundamental for neuroscience. The globus pallidus external segment (GPe), also referred to as the globus pallidus in rodents, is a large nucleus located in the core of the basal ganglia whose circuitry is implicated in action control, decision-making and reward. Although considerable progress has been made in characterizing different GPe neuronal subtypes, no work has directly attempted to characterize these neurons in non-transgenic mice. Here, we provide data showing the degree of overlap in expression of neuronal PAS domain protein (Npas1), LIM homeobox 6 (Lhx6), parvalbumin (PV) and transcription factor FoxP2 biomarkers in mouse GPe neurons. We used an unbiased statistical method to classify neurons based on electrophysiological properties from nearly 200 neurons from C57BL/6J mice. In addition, we examined the subregion distribution of the neuronal subtypes. Cluster analysis using firing rate and hyperpolarization-induced membrane potential sag variables revealed three distinct neuronal clusters: type 1, characterized by low firing rate and small sag potential; type 2, with low firing rate and larger sag potential; and type 3, with high firing rate and small sag potential. We used other electrophysiological variables and data from marker-expressing neurons to evaluate the clusters. We propose that the GPe GABAergic neurons should be classified into three subgroups: arkypallidal, low-firing prototypical and high-firing prototypical neurons. This work will help researchers identify GPe neuron subtypes when transgenic mice with labelled neurons cannot be used.
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http://dx.doi.org/10.1113/JP276079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117588PMC
September 2018
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