Binge-like alcohol drinking remodels the inhibitory microcircuitry of the prelimbic cortex in male and female mice

Eva C. Bach & Jeffrey L. Weiner

doi : 10.1038/s41386-021-01103-5

Neuropsychopharmacology volume 46, pages1859–1860 (2021)

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Interpreting weights of multimodal machine learning models—problems and pitfalls

Nils Ralf Winter, Janik Goltermann, Udo Dannlowski & Tim Hahn

doi : 10.1038/s41386-021-01030-5

Neuropsychopharmacology volume 46, pages1861–1862 (2021)

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Reply to Winter et al: Interpreting weights of multimodal machine learning models—problems and pitfalls

Matthew Price, Nicholas Allgaier & Hugh Garavan

doi : 10.1038/s41386-021-01082-7

Neuropsychopharmacology volume 46, page1863 (2021)

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Astrocyte-neuron signaling in the mesolimbic dopamine system: the hidden stars of dopamine signaling

Michelle Corkrum & Alfonso Araque

doi : 10.1038/s41386-021-01090-7

Neuropsychopharmacology volume 46, pages1864–1872 (2021)

Astrocytes are fundamental components of brain information processing and possess the ability to respond to synaptic signaling with increases in cytoplasmic calcium and modulate neuronal activity with the subsequent release of neuroactive transmitters. Dopamine signaling is essential for brain physiology and pathology, participating in learning and memory, motor control, neurological diseases, and psychiatric diseases, and astrocytes are emerging as a key cellular target of dopamine signaling. The present review will examine evidence revealing that astrocytes respond to dopamine and modulate information processing in the primary brain regions implicated in the mesolimbic dopamine system. Astrocytes exhibit circuit-specific modulation of neuronal networks and have the potential to serve as a therapeutic target for interventions designed for dopamine pathologies.

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Neurobiology of loneliness: a systematic review

Jeffrey A. Lam, Emily R. Murray, Kasey E. Yu, Marina Ramsey, Tanya T. Nguyen, Jyoti Mishra, Brian Martis, Michael L. Thomas & Ellen E. Lee

doi : 10.1038/s41386-021-01058-7

Neuropsychopharmacology volume 46, pages1873–1887 (2021)

Loneliness is associated with increased morbidity and mortality. Deeper understanding of neurobiological mechanisms underlying loneliness is needed to identify potential intervention targets. We did not find any systematic review of neurobiology of loneliness. Using MEDLINE and PsycINFO online databases, we conducted a search for peer-reviewed publications examining loneliness and neurobiology. We identified 41 studies (n?=?16,771 participants) that had employed various methods including computer tomography (CT), structural magnetic resonance imaging (MRI), functional MRI (fMRI), electroencephalography (EEG), diffusion tensor imaging (DTI), single-photon emission computed tomography (SPECT), positron emission tomography (PET), and post-mortem brain tissue RNA analysis or pathological analysis. Our synthesis of the published findings shows abnormal structure (gray matter volume or white matter integrity) and/or activity (response to pleasant versus stressful images in social versus nonsocial contexts) in the prefrontal cortex (especially medial and dorsolateral), insula (particularly anterior), amygdala, hippocampus, and posterior superior temporal cortex. The findings related to ventral striatum and cerebellum were mixed. fMRI studies reported links between loneliness and differential activation of attentional networks, visual networks, and default mode network. Loneliness was also related to biological markers associated with Alzheimer’s disease (e.g., amyloid and tau burden). Although the published investigations have limitations, this review suggests relationships of loneliness with altered structure and function in specific brain regions and networks. We found a notable overlap in the regions involved in loneliness and compassion, the two personality traits that are inversely correlated in previous studies. We have offered recommendations for future research studies of neurobiology of loneliness.

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Examination of the association between exposure to childhood maltreatment and brain structure in young adults: a machine learning analysis

Matthew Price, Matthew Albaugh, Sage Hahn, Anthony C. Juliano, Negar Fani, Zoe M. F. Brier, Alison C. Legrand, Katherine van Stolk-Cooke, Bader Chaarani, Alexandra Potter, Kelly Peck, Nicholas Allgaier, Tobias Banaschewski, Arun L. W. Bokde, Erin Burke Quinlan, Sylvane Desrivières, Herta Flor, Antoine Grigis, Penny Gowland, Andreas Heinz, Bernd Ittermann, Jean-Luc Martinot, Marie-Laure Paillère, Eric Artiges, Frauke Nees, Dimitri Papadopoulos Orfanos, Luise Poustka, Sarah Hohmann, Juliane H. Fröhner, Michael N. Smolka, Henrik Walter, Robert Whelan, Gunter Schumann & Hugh Garavan

doi : 10.1038/s41386-021-00987-7

Neuropsychopharmacology volume 46, pages1888–1894 (2021)

Exposure to maltreatment during childhood is associated with structural changes throughout the brain. However, the structural differences that are most strongly associated with maltreatment remain unclear given the limited number of whole-brain studies. The present study used machine learning to identify if and how brain structure distinguished young adults with and without a history of maltreatment. Young adults (ages 18–21, n?=?384) completed an assessment of childhood trauma exposure and a structural MRI as part of the IMAGEN study. Elastic net regularized regression was used to identify the structural features that identified those with a history of maltreatment. A generalizable model that included 7 cortical thicknesses, 15 surface areas, and 5 subcortical volumes was identified (area under the receiver operating characteristic curve?=?0.71, p?<?0.001). Those with a maltreatment history had reduced surface areas and cortical thicknesses primarily in fronto-temporal regions. This group also had larger cortical thicknesses in occipital regions and surface areas in frontal regions. The results suggest childhood maltreatment is associated with multiple measures of structure throughout the brain. The use of a large sample without exposure to adulthood trauma provides further evidence for the unique contribution of childhood trauma to brain structure. The identified regions overlapped with regions associated with psychopathology in adults with maltreatment histories, which offers insights as to how these disorders manifest.

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Identification of transdiagnostic psychiatric disorder subtypes using unsupervised learning

Helena Pelin, Marcus Ising, Frederike Stein, Susanne Meinert, Tina Meller, Katharina Brosch, Nils R. Winter, Axel Krug, Ramona Leenings, Hannah Lemke, Igor Nenadi?, Stefanie Heilmann-Heimbach, Andreas J. Forstner, Markus M. Nöthen, Nils Opel, Jonathan Repple, Julia Pfarr, Kai Ringwald, Simon Schmitt, Katharina Thiel, Lena Waltemate, Alexandra Winter, Fabian Streit, Stephanie Witt, Marcella Rietschel, Udo Dannlowski, Tilo Kircher, Tim Hahn, Bertram Müller-Myhsok & Till F. M. Andlauer

doi : 10.1038/s41386-021-01051-0

Neuropsychopharmacology volume 46, pages1895–1905 (2021)

Psychiatric disorders show heterogeneous symptoms and trajectories, with current nosology not accurately reflecting their molecular etiology and the variability and symptomatic overlap within and between diagnostic classes. This heterogeneity impedes timely and targeted treatment. Our study aimed to identify psychiatric patient clusters that share clinical and genetic features and may profit from similar therapies. We used high-dimensional data clustering on deep clinical data to identify transdiagnostic groups in a discovery sample (N?=?1250) of healthy controls and patients diagnosed with depression, bipolar disorder, schizophrenia, schizoaffective disorder, and other psychiatric disorders. We observed five diagnostically mixed clusters and ordered them based on severity. The least impaired cluster 0, containing most healthy controls, showed general well-being. Clusters 1–3 differed predominantly regarding levels of maltreatment, depression, daily functioning, and parental bonding. Cluster 4 contained most patients diagnosed with psychotic disorders and exhibited the highest severity in many dimensions, including medication load. Depressed patients were present in all clusters, indicating that we captured different disease stages or subtypes. We replicated all but the smallest cluster 1 in an independent sample (N?=?622). Next, we analyzed genetic differences between clusters using polygenic scores (PGS) and the psychiatric family history. These genetic variables differed mainly between clusters 0 and 4 (prediction area under the receiver operating characteristic curve (AUC)?=?81%; significant PGS: cross-disorder psychiatric risk, schizophrenia, and educational attainment). Our results confirm that psychiatric disorders consist of heterogeneous subtypes sharing molecular factors and symptoms. The identification of transdiagnostic clusters advances our understanding of the heterogeneity of psychiatric disorders and may support the development of personalized treatments.

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Somatostatin neurons control an alcohol binge drinking prelimbic microcircuit in mice

Nigel C. Dao, Dakota F. Brockway, Malini Suresh Nair, Avery R. Sicher & Nicole A. Crowley

doi : 10.1038/s41386-021-01050-1

Neuropsychopharmacology volume 46, pages1906–1917 (2021)

Somatostatin (SST) neurons have been implicated in a variety of neuropsychiatric disorders such as depression and anxiety, but their role in substance use disorders, including alcohol use disorder (AUD), is not fully characterized. Here, we found that repeated cycles of alcohol binge drinking via the Drinking-in-the-Dark (DID) model led to hypoactivity of SST neurons in the prelimbic (PL) cortex by diminishing their action potential firing capacity and excitatory/inhibitory transmission dynamic. We examined their role in regulating alcohol consumption via bidirectional chemogenetic manipulation. Both hM3Dq-induced excitation and KORD-induced silencing of PL SST neurons reduced alcohol binge drinking in males and females, with no effect on sucrose consumption. Alcohol binge drinking disinhibited pyramidal neurons by augmenting SST neurons-mediated GABA release and synaptic strength onto other GABAergic populations and reducing spontaneous inhibitory transmission onto pyramidal neurons. Pyramidal neurons additionally displayed increased intrinsic excitability. Direct inhibition of PL pyramidal neurons via hM4Di was sufficient to reduce alcohol binge drinking. Together these data revealed an SST-mediated microcircuit in the PL that modulates the inhibitory dynamics of pyramidal neurons, a major source of output to subcortical targets to drive reward-seeking behaviors and emotional response.

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The role of anterior insula–brainstem projections and alpha-1 noradrenergic receptors for compulsion-like and alcohol-only drinking

Thatiane De Oliveira Sergio, Kelly Lei, Claudina Kwok, Shahbaj Ghotra, Scott A. Wegner, Margaret Walsh, Jaclyn Waal, David Darevsky & Frederic W. Hopf

doi : 10.1038/s41386-021-01071-w

Neuropsychopharmacology volume 46, pages1918–1926 (2021)

Compulsion-like alcohol drinking (CLAD), where consumption continues despite negative consequences, is a major obstacle to treating alcohol use disorder. The locus coeruleus area in the brainstem and norepinephrine receptor (NER) signaling in forebrain cortical regions have been implicated in adaptive responding under stress, which is conceptually similar to compulsion-like responding (adaptive responding despite the presence of stress or conflict). Thus, we examined whether anterior insula (aINS)-to-brainstem connections and alpha-1 NERs regulated compulsion-like intake and alcohol-only drinking (AOD). Halorhodopsin inhibition of aINS–brainstem significantly reduced CLAD, with no effect on alcohol-only or saccharin intake, suggesting a specific aINS–brainstem role in aversion-resistant drinking. In contrast, prazosin inhibition of alpha-1 NERs systemically reduced both CLAD and AOD. Similar to systemic inhibition, intra-aINS alpha-1-NER antagonism reduced both CLAD and AOD. Global aINS inhibition with GABAR agonists also strongly reduced both CLAD and AOD, without impacting saccharin intake or locomotion, while aINS inhibition of calcium-permeable AMPARs (with NASPM) reduced CLAD without impacting AOD. Finally, prazosin inhibition of CLAD and AOD was not correlated with each other, systemically or within aINS, suggesting the possibility that different aINS pathways regulate CLAD versus AOD, which will require further study to definitively address. Together, our results provide important new information showing that some aINS pathways (aINS–brainstem and NASPM-sensitive) specifically regulate compulsion-like alcohol consumption, while aINS more generally may contain parallel pathways promoting CLAD versus AOD. These findings also support the importance of the adaptive stress response system for multiple forms of alcohol drinking.

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Sex- and subtype-specific adaptations in excitatory signaling onto deep-layer prelimbic cortical pyramidal neurons after chronic alcohol exposure

Benjamin A. Hughes, Todd K. O’Buckley, Giorgia Boero, Melissa A. Herman & A. Leslie Morrow

doi : 10.1038/s41386-021-01034-1

Neuropsychopharmacology volume 46, pages1927–1936 (2021)

Long-term alcohol use results in behavioral deficits including impaired working memory, elevated anxiety, and blunted inhibitory control that is associated with prefrontal cortical (PFC) dysfunction. Preclinical observations demonstrate multiple impairments in GABAergic neurotransmission onto deep-layer principal cells (PCs) in the prelimbic cortex that suggest dependence-related cortical dysfunction is the product of elevated excitability in these cells. Despite accumulating evidence showing alcohol-induced changes in interneuron signaling onto PCs differ between sexes, there is limited data explicitly evaluating sex-specific ethanol effects on excitatory signaling onto deep-layer PCs that may further contribute to deficits in PFC-dependent behaviors. To address this, we conducted electrophysiological and behavioral tests in both male and female Sprague-Dawley rats to evaluate the effects of chronic ethanol exposure. Among our observations, we report a marked enhancement in glutamatergic signaling onto deep-layer PCs in male, but not female, rats after alcohol exposure. This phenomenon was furthermore specific to a sub-class of PC, sub-cortically projecting Type-A cells, and coincided with enhanced anxiety-like behavior, but no observable deficit in working memory. In contrast, female rats displayed alcohol-induced facilitation in working memory performance with no change in expression of anxiety-like behavior. Together, these results suggest fundamental differences in alcohol effects on cell activity, cortical sub-circuits, and PFC-dependent behaviors across male and female rats.

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Sexually dimorphic prelimbic cortex mechanisms play a role in alcohol dependence: protection by endostatin

Yosef Avchalumov, Alison D. Kreisler, Nancy Xing, Amin A. Shayan, Tejash Bharadwaj, Jacob R. Watson, Britta Sibley, Sucharita S. Somkuwar, Wulfran Trenet, Sumaiya Olia, Juan C. Piña-Crespo, Marisa Roberto & Chitra D. Mandyam

doi : 10.1038/s41386-021-01075-6

Neuropsychopharmacology volume 46, pages1937–1949 (2021)

Angiogenesis or proliferation of endothelial cells plays a role in brain microenvironment homeostasis. Previously we have shown enhanced expression of markers of angiogenesis in the medial prefrontal cortex during abstinence in an animal model of ethanol dependence induced by chronic intermittent ethanol vapor (CIE) and ethanol drinking (ED) procedure. Here we report that systemic injections of the angiogenesis inhibitor endostatin reduced relapse to drinking behavior in female CIE-ED rats without affecting relapse to drinking in male CIE-ED rats, and female and male nondependent ED rats. Endostatin did not alter relapse to sucrose drinking in both sexes. Endostatin reduced expression of platelet endothelial cell adhesion molecule-1 (PECAM-1) in all groups; however, rescued expression of tight junction protein claudin-5 in the prelimbic cortex (PLC) of female CIE-ED rats. In both sexes, CIE-ED enhanced microglial activation in the PLC and this was selectively prevented by endostatin in female CIE-ED rats. Endostatin prevented CIE-ED-induced enhanced NF-kB activity and expression and Fos expression in females and did not alter reduced Fos expression in males. Analysis of synaptic processes within the PLC revealed sexually dimorphic adaptations, with CIE-ED reducing synaptic transmission and altering synaptic plasticity in the PLC in females, and increasing synaptic transmission in males. Endostatin prevented the neuroadaptations in the PLC in females via enhancing phosphorylation of CaMKII, without affecting the neuroadaptations in males. Our multifaceted approach is the first to link PLC endothelial cell damage to the behavioral, neuroimmune, and synaptic changes associated with relapse to ethanol drinking in female subjects, and provides a new therapeutic strategy to reduce relapse in dependent subjects.

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Activation of hypothalamic oxytocin neurons reduces binge-like alcohol drinking through signaling at central oxytocin receptors

Courtney E. King, William C. Griffin, Marcelo F. Lopez & Howard C. Becker

doi : 10.1038/s41386-021-01046-x

Neuropsychopharmacology volume 46, pages1950–1957 (2021)

Preclinical and clinical evidence suggests that exogenous administration of oxytocin (OT) may hold promise as a therapeutic strategy for reducing heavy alcohol drinking. However, it remains unknown whether these effects are mediated by stimulation of endogenous sources of OT and signaling at oxytocin receptors (OTR) in brain or in the periphery. To address this question, we employed a targeted chemogenetic approach to examine whether selective activation of OT-containing neurons in the paraventricular nucleus of the hypothalamus (PVN) alters alcohol consumption in a binge-like drinking (“Drinking-in-the-Dark”; DID) model. Adult male Oxt-IRES-Cre mice received bilateral infusion of a Cre-dependent virus containing an excitatory DREADD (AAV8-hSyn-DIO-hM3Dq-mCherry) or control virus (AAV8-hSyn-DIO-mCherry) into the PVN. Chemogenetic activation of PVNOT+ neurons following clozapine-N-oxide injection reduced binge-like alcohol drinking in a similar manner as systemic administration of the neuropeptide. Pretreatment with a brain-penetrant OTR antagonist (L-368,899) reversed this effect while systemic administration of a peripherally restricted OTR antagonist (Atosiban) did not alter reduced alcohol drinking following chemogenetic activation of PVNOT+ neurons. Altogether, these data are the first to demonstrate that targeted activation of hypothalamic (endogenous) OT reduces alcohol consumption, providing further evidence that this neuropeptide plays a role in regulation of alcohol self-administration behavior. Further, results indicate that the ability OT to reduce alcohol drinking is mediated by signaling at OTR in the brain.

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Early-life oxytocin attenuates the social deficits induced by caesarean-section delivery in the mouse

Livia H. Morais, Anna V. Golubeva, Sophie Casey, Karen A. Scott, Ana Paula Ramos Costa, Gerard M. Moloney, Timothy G. Dinan & John F. Cryan

doi : 10.1038/s41386-021-01040-3

Neuropsychopharmacology volume 46, pages1958–1968 (2021)

The oxytocin (OXT) system has been strongly implicated in the regulation of social behaviour and anxiety, potentially contributing to the aetiology of a wide range of neuropathologies. Birth by Caesarean-section (C-section) results in alterations in microbiota diversity in early-life, alterations in brain development and has recently been associated with long-term social and anxiety-like behaviour deficits. In this study, we assessed whether OXT intervention in the early postnatal period could reverse C-section-mediated effects on behaviour, and physiology in early life and adulthood. Following C-section or per vaginum birth, pups were administered with OXT (0.2 or 2??g/20??l; s.c.) or saline daily from postnatal days 1–5. We demonstrate that early postnatal OXT treatment has long-lasting effects reversing many of the effects of C-section on mouse behaviour and physiology. In early-life, high-dose OXT administration attenuated C-section-mediated maternal attachment impairments. In adulthood, low-dose OXT restored social memory deficits, some aspects of anxiety-like behaviour, and improved gastrointestinal transit. Furthermore, as a consequence of OXT intervention in early life, OXT plasma levels were increased in adulthood, and dysregulation of the immune response in C-section animals was attenuated by both doses of OXT treatment. These findings indicate that there is an early developmental window sensitive to manipulations of the OXT system that can prevent lifelong behavioural and physiological impairments associated with mode of birth.

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Inactivation of the infralimbic cortex decreases discriminative stimulus-controlled relapse to cocaine seeking in rats

Rajtarun Madangopal, Leslie A. Ramsey, Sophia J. Weber, Megan B. Brenner, Veronica A. Lennon, Olivia R. Drake, Lauren E. Komer, Brendan J. Tunstall, Jennifer M. Bossert, Yavin Shaham & Bruce T. Hope

doi : 10.1038/s41386-021-01067-6

Neuropsychopharmacology volume 46, pages1969–1980 (2021)

Persistent susceptibility to cue-induced relapse is a cardinal feature of addiction. Discriminative stimuli (DSs) are one type of drug-associated cue that signal drug availability (DS+) or unavailability (DS?) and control drug seeking prior to relapse. We previously established a trial-based procedure in rats to isolate DSs from context, conditioned stimuli, and other drug-associated cues during cocaine self-administration and demonstrated DS-controlled cocaine seeking up to 300 abstinence days. The behavioral and neural mechanisms underlying trial-based DS-control of drug seeking have rarely been investigated. Here we show that following discrimination training in our trial-based procedure, the DS+ and DS? independently control the expression and suppression of cocaine seeking during abstinence. Using microinjections of GABAA?+?GABAB receptor agonists (muscimol?+?baclofen) in medial prefrontal cortex, we report that infralimbic, but not prelimbic, subregion of medial prefrontal cortex is critical to persistent DS-controlled relapse to cocaine seeking after prolonged abstinence, but not DS-guided discriminated cocaine seeking or DS-controlled cocaine self-admininstration. Finally, using ex vivo whole-cell recordings from pyramidal neurons in the medial prefrontal cortex, we demonstrate that the disruption of DS-controlled cocaine seeking following infralimbic cortex microinjections of muscimol+baclofen is likely a result of suppression of synaptic transmission in the region via a presynaptic mechanism of action.

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Dissociable control of ?-opioid-driven hyperphagia vs. food impulsivity across subregions of medial prefrontal, orbitofrontal, and insular cortex

Juliana L. Giacomini, Emma Geiduschek, Ryan A. Selleck, Ken Sadeghian & Brian A. Baldo

doi : 10.1038/s41386-021-01068-5

Neuropsychopharmacology volume 46, pages1981–1989 (2021)

This study explored potentially dissociable functions of mu-opioid receptor (µ-OR) signaling across different cortical territories in the control of anticipatory activity directed toward palatable food, consumption, and impulsive food-seeking behavior in male rats. The µ-OR agonist, DAMGO ([D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin), was infused into infralimbic cortex (ILC), prelimbic cortex (PrL), medial and lateral ventral orbitofrontal cortices (VMO, VLO), and agranular/dysgranular insular (AI/DI) cortex of rats. Intra-ILC DAMGO markedly enhanced contact with a see-through screen behind which sucrose pellets were sequestered; in addition, rats having received intra-ILC and intra-VMO DAMGO exhibited locomotor hyperactivity while the screen was in place. Upon screen removal, intra-ILC and -VMO-treated rats emitted numerous, brief sucrose-intake bouts (yielding increased overall intake) interspersed with significant hyperactivity. In contrast, intra-AI/DI-treated rats consumed large amounts of sucrose in long, uninterrupted bouts with no anticipatory hyperactivity pre-screen removal. Intra-PrL and intra-VLO DAMGO altered neither pre-screen behavior nor sucrose intake. Finally, all rats were tested in a sucrose-reinforced differential reinforcement of low rates (DRL) task, which assesses the ability to advantageously withhold premature responses. DAMGO affected (impaired) DRL performance when infused into ILC only. These site-based dissociations reveal differential control of µ-OR-modulated appetitive/approach vs. consummatory behaviors by ventromedial/orbitofrontal and insular networks, respectively, and suggest a unique role of ILC µ-ORs in modulating inhibitory control.

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Anterior cingulate cortex is necessary for spontaneous opioid withdrawal and withdrawal-induced hyperalgesia in male mice

Dillon S. McDevitt, Greer McKendrick & Nicholas M. Graziane

doi : 10.1038/s41386-021-01118-y

Neuropsychopharmacology volume 46, pages1990–1999 (2021)

The anterior cingulate cortex (ACC) is implicated in many pathologies, including depression, anxiety, substance-use disorders, and pain. There is also evidence from brain imaging that the ACC is hyperactive during periods of opioid withdrawal. However, there are limited data contributing to our understanding of ACC function at the cellular level during opioid withdrawal. Here, we address this issue by performing ex vivo electrophysiological analysis of thick-tufted, putative dopamine D2 receptor expressing, layer V pyramidal neurons in the ACC (ACC L5 PyNs) in a mouse model of spontaneous opioid withdrawal. We found that escalating doses of morphine (20, 40, 60, 80, and 100?mg/kg, i.p. on days 1–5, respectively) injected twice daily into male C57BL/6 mice evoked withdrawal behaviors and an associated withdrawal-induced mechanical hypersensitivity. Brain slices prepared 24?h following the last morphine injection showed increases in ACC L5 thick-tufted PyN-intrinsic membrane excitability, increases in membrane resistance, reductions in the rheobase, and reductions in HCN channel-mediated currents (IH). We did not observe changes in intrinsic or synaptic properties on thin-tufted, dopamine D1-receptor-expressing ACC L5 PyNs recorded from male Drd1a-tdTomato transgenic mice. In addition, we found that chemogenetic inhibition of the ACC blocked opioid-induced withdrawal and withdrawal-induced mechanical hypersensitivity. These results demonstrate that spontaneous opioid withdrawal alters neuronal properties within the ACC and that ACC activity is necessary to control behaviors associated with opioid withdrawal and withdrawal-induced mechanical hypersensitivity. The ability of the ACC to regulate both withdrawal behaviors and withdrawal-induced mechanical hypersensitivity suggests overlapping mechanisms between two seemingly distinguishable behaviors. This commonality potentially suggests that the ACC is a locus for multiple withdrawal symptoms.

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Systemic enhancement of serotonin signaling reverses social deficits in multiple mouse models for ASD

Jessica J. Walsh, Pierre Llorach, Daniel F. Cardozo Pinto, Wendy Wenderski, Daniel J. Christoffel, Juliana S. Salgado, Boris D. Heifets, Gerald R. Crabtree & Robert C. Malenka

doi : 10.1038/s41386-021-01091-6

Neuropsychopharmacology volume 46, pages2000–2010 (2021)

Autism spectrum disorder (ASD) is a common set of heterogeneous neurodevelopmental disorders resulting from a variety of genetic and environmental risk factors. A core feature of ASD is impairment in prosocial interactions. Current treatment options for individuals diagnosed with ASD are limited, with no current FDA-approved medications that effectively treat its core symptoms. We recently demonstrated that enhanced serotonin (5-HT) activity in the nucleus accumbens (NAc), via optogenetic activation of 5-HTergic inputs or direct infusion of a specific 5-HT1b receptor agonist, reverses social deficits in a genetic mouse model for ASD based on 16p11.2 copy number variation. Furthermore, the recreational drug MDMA, which is currently being evaluated in clinical trials, promotes sociability in mice due to its 5-HT releasing properties in the NAc. Here, we systematically evaluated the ability of MDMA and a selective 5-HT1b receptor agonist to rescue sociability deficits in multiple different mouse models for ASD. We find that MDMA administration enhances sociability in control mice and reverses sociability deficits in all four ASD mouse models examined, whereas administration of a 5-HT1b receptor agonist selectively rescued the sociability deficits in all six mouse models for ASD. These preclinical findings suggest that pharmacological enhancement of 5-HT release or direct 5-HT1b receptor activation may be therapeutically efficacious in ameliorating some of the core sociability deficits present across etiologically distinct presentations of ASD.

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Autistic-like behavior, spontaneous seizures, and increased neuronal excitability in a Scn8a mouse model

Jennifer C. Wong, Steven F. Grieco, Karoni Dutt, Lujia Chen, Jacquelyn T. Thelin, George Andrew S. Inglis, Shangrila Parvin, Sandra M. Garraway, Xiangmin Xu, Alan L. Goldin & Andrew Escayg

doi : 10.1038/s41386-021-00985-9

Neuropsychopharmacology volume 46, pages2011–2020 (2021)

Patients with SCN8A epileptic encephalopathy exhibit a range of clinical features, including multiple seizure types, movement disorders, and behavioral abnormalities, such as developmental delay, mild-to-severe intellectual disability, and autism. Recently, the de novo heterozygous SCN8A R1620L mutation was identified in an individual with autism, intellectual disability, and behavioral seizures without accompanying electrographic seizure activity. To date, the effects of SCN8A mutations that are primarily associated with behavioral abnormalities have not been studied in a mouse model. To better understand the phenotypic and functional consequences of the R1620L mutation, we used CRISPR/Cas9 technology to generate mice expressing the corresponding SCN8A amino acid substitution. Homozygous mutants exhibit tremors and a maximum lifespan of 22 days, while heterozygous mutants (RL/+) exhibit autistic-like behaviors, such as hyperactivity and learning and social deficits, increased seizure susceptibility, and spontaneous seizures. Current clamp analyses revealed a reduced threshold for firing action potentials in heterozygous CA3 pyramidal neurons and reduced firing frequency, suggesting that the R1620L mutation has both gain- and loss-of-function effects. In vivo calcium imaging using miniscopes in freely moving RL/+ mutants showed hyperexcitability of cortical excitatory neurons that is likely to increase seizure susceptibility. Finally, we found that oxcarbazepine and Huperzine A, a sodium channel blocker and reversible acetylcholinesterase inhibitor, respectively, were capable of conferring robust protection against induced seizures in RL/+ mutants. This mouse line will provide the opportunity to better understand the range of clinical phenotypes associated with SCN8A mutations and to develop new therapeutic approaches.

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Sex-dependent role for EPHB2 in brain development and autism-associated behavior

Ahlem Assali, Jennifer Y. Cho, Evgeny Tsvetkov, Abha R. Gupta & Christopher W. Cowan

doi : 10.1038/s41386-021-00986-8

Neuropsychopharmacology volume 46, pages2021–2029 (2021)

Autism spectrum disorder (ASD) is characterized by impairments in social communication and interaction and restricted, repetitive behaviors. It is frequently associated with comorbidities, such as attention-deficit hyperactivity disorder, altered sensory sensitivity, and intellectual disability. A de novo nonsense mutation in EPHB2 (Q857X) was discovered in a female patient with ASD [13], revealing EPHB2 as a candidate ASD risk gene. EPHB2 is a receptor tyrosine kinase implicated in axon guidance, synaptogenesis, and synaptic plasticity, positioning it as a plausible contributor to the pathophysiology of ASD and related disorders. In this study, we show that the Q857X mutation produced a truncated protein lacking forward signaling and that global disruption of one EphB2 allele (EphB2+/?) in mice produced several behavioral phenotypes reminiscent of ASD and common associated symptoms. EphB2+/? female, but not male, mice displayed increased repetitive behavior, motor hyperactivity, and learning and memory deficits, revealing sex-specific effects of EPHB2 hypofunction. Moreover, we observed a significant increase in the intrinsic excitability, but not excitatory/inhibitory ratio, of motor cortex layer V pyramidal neurons in EphB2+/? female, but not male, mice, suggesting a possible mechanism by which EPHB2 hypofunction may contribute to sex-specific motor-related phenotypes. Together, our findings suggest that EPHB2 hypofunction, particularly in females, is sufficient to produce ASD-associated behaviors and altered cortical functions in mice.

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Effects of visual attention modulation on dynamic functional connectivity during own-face viewing in body dysmorphic disorder

Wan-wa Wong, Joana Cabral, Riddhi Rane, Ronald Ly, Morten L. Kringelbach & Jamie D. Feusner

doi : 10.1038/s41386-021-01039-w

Neuropsychopharmacology volume 46, pages2030–2038 (2021)

Body dysmorphic disorder (BDD) is characterized by preoccupations with misperceptions of one’s physical appearance. Previous neuroimaging studies in BDD have yet to examine dynamic functional connectivity (FC) patterns between brain areas, necessary to capture changes in activity in response to stimuli and task conditions. We used Leading Eigenvector Dynamics Analysis to examine whole-brain dynamic FC from fMRI data during an own-face viewing task in 29 unmedicated adults with BDD with facial concerns and 30 healthy controls. The task involved two parts: (1) unconstrained, naturalistic viewing and (2) holding visual attention in the center of the image, to reduce scanning and fixation on perceived facial flaws. An FC state consisting of bilateral medial orbitofrontal cortex regions occurred significantly less often during the visual attention condition and afterward during the unconstrained face viewing in BDD participants, compared to the first unconstrained face viewing, a pattern that differed from controls. Moreover, the probability of this state during the second unconstrained face viewing was associated with severity of obsessions and compulsions and degree of poor insight in BDD, suggesting its clinical significance. These findings have implications for understanding the pathophysiology of own-face viewing in BDD and how it is affected by modification of viewing patterns, which may have implications for novel perceptual retraining treatment designs.

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