Bombesin-like peptide recruits disinhibitory cortical circuits and enhances fear memories.

Disinhibitory neurons throughout the mammalian cortex are powerful enhancers of circuit excitability and plasticity. The differential expression of neuropeptide receptors in disinhibitory, inhibitory, and excitatory neurons suggests that each circuit motif may be controlled by distinct neuropeptidergic systems. Here, we reveal that a bombesin-like neuropeptide, gastrin-releasing peptide (GRP), recruits disinhibitory cortical microcircuits through selective targeting and activation of vasoactive intestinal peptide (VIP)-expressing cells. Using a genetically encoded GRP sensor, optogenetic anterograde stimulation, and trans-synaptic tracing, we reveal that GRP regulates VIP cells most likely via extrasynaptic diffusion from several local and long-range sources. In vivo photometry and CRISPR-Cas9-mediated knockout of the GRP receptor (GRPR) in auditory cortex indicate that VIP cells are strongly recruited by novel sounds and aversive shocks, and GRP-GRPR signaling enhances auditory fear memories. Our data establish peptidergic recruitment of selective disinhibitory cortical microcircuits as a mechanism to regulate fear memories.

How Flies See Motion.

How neurons detect the direction of motion is a prime example of neural computation: Motion vision is found in the visual systems of virtually all sighted animals, it is important for survival, and it requires interesting computations with well-defined linear and nonlinear processing steps-yet the whole process is of moderate complexity. The genetic methods available in the fruit fly Drosophila and the charting of a connectome of its visual system have led to rapid progress and unprecedented detail in our understanding of how neurons compute the direction of motion in this organism. The picture that emerged incorporates not only the identity, morphology, and synaptic connectivity of each neuron involved but also its neurotransmitters, its receptors, and their subcellular localization. Together with the neurons' membrane potential responses to visual stimulation, this information provides the basis for a biophysically realistic model of the circuit that computes the direction of visual motion.

Functional specialization of hippocampal somatostatin-expressing interneurons.

Hippocampal somatostatin-expressing (Sst) GABAergic interneurons (INs) exhibit considerable anatomical and functional heterogeneity. Recent single-cell transcriptome analyses have provided a comprehensive Sst-IN subpopulations census, a plausible molecular ground truth of neuronal identity whose links to specific functionality remain incomplete. Here, we designed an approach to identify and access subpopulations of Sst-INs based on transcriptomic features. Four mouse models based on single or combinatorial Cre- and Flp- expression differentiated functionally distinct subpopulations of CA1 hippocampal Sst-INs that largely tiled the morpho-functional parameter space of the Sst-INs superfamily. Notably, the Sst;;Tac1 intersection revealed a population of bistratified INs that preferentially synapsed onto fast-spiking interneurons (FS-INs) and were sufficient to interrupt their firing. In contrast, the Ndnf;;Nkx2-1 intersection identified a population of oriens lacunosum-moleculare INs that predominantly targeted CA1 pyramidal neurons, avoiding FS-INs. Overall, our results provide a framework to translate neuronal transcriptomic identity into discrete functional subtypes that capture the diverse specializations of hippocampal Sst-INs.

Regulation of the Mouse Ventral Tegmental Area by Melanin-Concentrating Hormone.

Melanin-concentrating hormone (MCH) acts via its sole receptor MCHR1 in rodents and is an important regulator of homeostatic behaviors like feeding, sleep, and mood to impact overall energy balance. The loss of MCH signaling by MCH or MCHR1 deletion produces hyperactive mice with increased energy expenditure, and these effects are consistently associated with a hyperdopaminergic state. We recently showed that MCH suppresses dopamine release in the nucleus accumbens, which principally receives dopaminergic projections from the ventral tegmental area (VTA), but the mechanisms underlying MCH-regulated dopamine release are not clearly defined. MCHR1 expression is widespread and includes dopaminergic VTA cells. However, as the VTA is a neurochemically diverse structure, we assessed Mchr1 gene expression at glutamatergic, GABAergic, and dopaminergic VTA cells and determined if MCH inhibited the activity of VTA cells and/or their local microcircuit. Mchr1 expression was robust in major VTA cell types, including most dopaminergic (78%) or glutamatergic cells (52%) and some GABAergic cells (38%). Interestingly, MCH directly inhibited dopaminergic and GABAergic cells but did not regulate the activity of glutamatergic cells. Rather, MCH produced a delayed increase in excitatory input to dopamine cells and a corresponding decrease in GABAergic input to glutamatergic VTA cells. Our findings suggested that MCH may acutely suppress dopamine release while disinhibiting local glutamatergic signaling to restore dopamine levels. This indicated that the VTA is a target of MCH action, which may provide bidirectional regulation of energy balance.

Extracellular glutamate and GABA transients at the transition from interictal spiking to seizures.

Focal epilepsy is associated with intermittent brief population discharges (interictal spikes), which resemble sentinel spikes that often occur at the onset of seizures. Why interictal spikes self-terminate whilst seizures persist and propagate is incompletely understood. We used fluorescent glutamate and GABA sensors in an awake rodent model of neocortical seizures to resolve the spatiotemporal evolution of both neurotransmitters in the extracellular space. Interictal spikes were accompanied by brief glutamate transients which were maximal at the initiation site and rapidly propagated centrifugally. GABA transients lasted longer than glutamate transients and were maximal ∼1.5 mm from the focus where they propagated centripetally. Prior to seizure initiation GABA transients were attenuated, whilst glutamate transients increased, consistent with a progressive failure of local inhibitory restraint. As seizures increased in frequency, there was a gradual increase in the spatial extent of spike-associated glutamate transients associated with interictal spikes. Neurotransmitter imaging thus reveals a progressive collapse of an annulus of feed-forward GABA release, allowing seizures to escape from local inhibitory restraint.

Atrophy network mapping of clinical subtypes and main symptoms in frontotemporal dementia.

Frontotemporal Dementia (FTD) is a disease of high heterogeneity, apathy and disinhibition present in all subtypes of FTD and imposes a significant burden on families/society. Traditional neuroimaging analysis has limitations in elucidating the network localization due to individual clinical and neuroanatomical variability. The study aims to identify the atrophy network map associated with different FTD clinical subtypes and determine the specific localization of the network for apathy and disinhibition. Eighty FTD patients [45 behavioral variant FTD (bvFTD) and 35 semantic variant progressive primary aphasia (svPPA)] and 58 healthy controls (HCs) at Xuanwu Hospital were enrolled as Dataset 1; 112 FTD patients including 50 bvFTD, 32 svPPA, and 30 non-fluent variant PPA (nfvPPA) cases, and 110 HCs from Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI) dataset were included as Dataset 2. Initially, single-subject atrophy maps were defined by comparing cortical thickness in each FTD patient versus HCs. Next, the network of brain regions functionally connected to each FTD patient's location of atrophy was determined using seed-based functional connectivity in a large (n = 1000) normative connectome. Finally, we used atrophy network mapping to define clinical subtype-specific network (45 bvFTD, 35 svPPA and 58 HCs in Dataset 1; 50 bvFTD, 32 svPPA, 30 nfvPPA and 110 HCs in Dataset 2) and symptom-specific networks [combined dataset 1 and 2, apathy without depression Vs non-apathy without depression (80:26), disinhibition Vs non-disinhibition (88:68)]. We compare the result with matched symptom networks derived from patients with focal brain lesions or conjunction analysis. Through the analysis of two datasets, we identified heterogeneity in atrophy patterns among FTD patients. However, these atrophy patterns are connected to a common brain network. The primary regions affected by atrophy in FTD included the frontal and temporal lobes, particularly the anterior temporal lobe. bvFTD connects to frontal and temporal cortical areas, svPPA mainly impacts the anterior temporal region, and nfvPPA targets the inferior frontal gyrus and precentral cortex regions. The apathy-specific network was localized in the orbital frontal cortex and ventral striatum, while the disinhibition-specific network was localized in the bilateral orbital frontal gyrus and right temporal lobe. Apathy and disinhibition atrophy networks resemble known motivational and criminal lesion networks respectively. A significant correlation was found between the apathy/disinhibition scores and functional connectivity between atrophy maps and the peak of the networks. This study localizes the common network of clinical subtypes and main symptoms in FTD, guiding future FTD neuromodulation interventions.

Changes in functional connectivity and structural covariance between the fronto-parietal network and medial orbitofrontal cortex are associated with disinhibition in restrained eaters.

Disinhibition, characterized by a loss of dietary control, is a significant risk factor for diet failure and the onset of eating disorders in restrained eaters. This study employs resting-state functional connectivity and structural covariance network analyses to explore the neural associations underlying this behavior. By analyzing functional MRI data from 63 female college students, we found that increased disinhibition correlates with enhanced functional connectivity between the medial orbitofrontal cortex and key components of the inhibition system, particularly within the fronto-parietal network. Moreover, we observed a relationship between the structural covariance of the medial orbitofrontal cortex and the inferior parietal lobule and the severity of disinhibition. Importantly, the functional connectivity between the medial orbitofrontal cortex and the inferior parietal lobule predicts the severity of binge eating symptoms in these individuals. These findings indicate that imbalances in the interaction between the brain's reward and inhibition systems can lead to dietary failures and eating disorders, emphasizing the need for targeted interventions.

Disinhibition of Mesolimbic Dopamine Circuit by the Lateral Hypothalamus Regulates Pain Sensation.

Our recent study demonstrated the critical role of the mesolimbic dopamine (DA) circuit and its brain-derived neurotropic factor (BDNF) signaling in mediating neuropathic pain. The present study aims to investigate the functional role of GABAergic inputs from the lateral hypothalamus (LH) to the ventral tegmental area (VTA; LHGABA→VTA) in regulating the mesolimbic DA circuit and its BDNF signaling underlying physiological and pathologic pain. We demonstrated that optogenetic manipulation of the LHGABA→VTA projection bidirectionally regulated pain sensation in naive male mice. Optogenetic inhibition of this projection generated an analgesic effect in mice with pathologic pain induced by chronic constrictive injury (CCI) of the sciatic nerve and persistent inflammatory pain by complete Freund's adjuvant (CFA). Trans-synaptic viral tracing revealed a monosynaptic connection between LH GABAergic neurons and VTA GABAergic neurons. Functionally, in vivo calcium/neurotransmitter imaging showed an increased DA neuronal activity, decreased GABAergic neuronal activity in the VTA, and increased dopamine release in the NAc, in response to optogenetic activation of the LHGABA→VTA projection. Furthermore, repeated activation of the LHGABA→VTA projection was sufficient to increase the expression of mesolimbic BDNF protein, an effect seen in mice with neuropathic pain. Inhibition of this circuit induced a decrease in mesolimbic BDNF expression in CCI mice. Interestingly, the pain behaviors induced by activation of the LHGABA→VTA projection could be prevented by pretreatment with intra-NAc administration of ANA-12, a TrkB receptor antagonist. These results demonstrated that LHGABA→VTA projection regulated pain sensation by targeting local GABAergic interneurons to disinhibit the mesolimbic DA circuit and regulating accumbal BDNF release.SIGNIFICANCE STATEMENT The mesolimbic dopamine (DA) system and its brain-derived neurotropic factor (BDNF) signaling have been implicated in pain regulation, however, underlying mechanisms remain poorly understood. The lateral hypothalamus (LH) sends different afferent fibers into and strongly influences the function of mesolimbic DA system. Here, utilizing cell type- and projection-specific viral tracing, optogenetics, in vivo calcium and neurotransmitter imaging, our current study identified the LHGABA→VTA projection as a novel neural circuit for pain regulation, possibly by targeting the VTA GABA-ergic neurons to disinhibit mesolimbic pathway-specific DA release and BDNF signaling. This study provides a better understanding of the role of the LH and mesolimbic DA system in physiological and pathological pain.

Short- and Long-Term High-Fat Diet Exposure Differentially Alters Phasic and Tonic GABAergic Signaling onto Lateral Orbitofrontal Pyramidal Neurons.

The chronic consumption of caloric dense high-fat foods is a major contributor to increased body weight, obesity, and other chronic health conditions. The orbitofrontal cortex (OFC) is critical in guiding decisions about food intake and is altered with diet-induced obesity. Obese rodents have altered morphologic and synaptic electrophysiological properties in the lateral orbitofrontal cortex (lOFC). Yet the time course by which exposure to a high-fat diet (HFD) induces these changes is poorly understood. Here, male mice are exposed to either short-term (7 d) or long-term (90 d) HFD. Long-term HFD exposure increases body weight, and glucose signaling compared with short-term HFD or a standard control diet (SCD). Both short and long-term HFD exposure increased the excitability of lOFC pyramidal neurons. However, phasic and tonic GABAergic signaling was differentially altered depending on HFD exposure length, such that tonic GABAergic signaling was decreased with early exposure to the HFD and phasic signaling was changed with long-term diet exposure. Furthermore, alterations in the short-term diet exposure were transient, as removal of the diet restored electrophysiological characteristics similar to mice fed SCD, whereas long-term HFD electrophysiological changes were persistent and remained after HFD removal. Finally, we demonstrate that changes in reward devaluation occur early with diet exposure. Together, these results suggest that the duration of HFD exposure differentially alters lOFC function and provides mechanistic insights into the susceptibility of the OFC to impairments in outcome devaluation.SIGNIFICANCE STATEMENT This study provides mechanistic insight on the impact of short-term and long-term high-fat diet (HFD) exposure on GABAergic function in the lateral orbitofrontal cortex (lOFC), a region known to guide decision-making. We find short-term HFD exposure induces transient changes in firing and tonic GABA action on lOFC pyramidal neurons, whereas long-term HFD induces obesity and has lasting changes on firing, tonic GABA and inhibitory synaptic transmission onto lOFC neurons. Given that GABAergic signaling in the lOFC can influence decision-making around food, these results have important implications in present society as palatable energy dense foods are abundantly available.

Cell type-specific and frequency-dependent centrifugal modulation in olfactory bulb output neurons in vivo.

Mitral/tufted cells (M/TCs) form complex local circuits with interneurons in the olfactory bulb and are powerfully inhibited by these interneurons. The horizontal limb of the diagonal band of Broca (HDB), the only GABAergic/inhibitory source of centrifugal circuit with the olfactory bulb, is known to target olfactory bulb interneurons, and we have shown targeting also to olfactory bulb glutamatergic neurons in vitro. However, the net efficacy of these circuits under different patterns of activation in vivo and the relative balance between the various targeted intact local and centrifugal circuits was the focus of this study. Here channelrhodopsin-2 (ChR2) was expressed in HDB GABAergic neurons to investigate the short-term plasticity of HDB-activated disinhibitory rebound excitation of M/TCs. Optical activation of HDB interneurons increased spontaneous M/TC firing without odor presentation and increased odor-evoked M/TC firing. HDB activation induced disinhibitory rebound excitation (burst or cluster of spiking) in all classes of M/TCs. This excitation was frequency dependent, with short-term facilitation only at higher HDB stimulation frequency (5 Hz and above). However, frequency-dependent HDB regulation was more potent in the deeper layer M/TCs compared with more superficial layer M/TCs. In all neural circuits the balance between inhibition and excitation in local and centrifugal circuits plays a critical functional role, and this patterned input-dependent regulation of inhibitory centrifugal inputs to the olfactory bulb may help maintain the precise balance across the populations of output neurons in different environmental odors, putatively to sharpen the enhancement of tuning specificity of individual or classes of M/TCs to odors.NEW & NOTEWORTHY Neuronal local circuits in the olfactory bulb are modulated by centrifugal long circuits. In vivo study here shows that inhibitory horizontal limb of the diagonal band of Broca (HDB) modulates all five types of mitral/tufted cells (M/TCs), by direct inhibitory circuits HDB → M/TCs and indirect disinhibitory long circuits HDB → interneurons → M/TCs. The HDB net effect exerts excitation in all types of M/TCs but more powerful in deeper layer output neurons as HDB activation frequency increases, which may sharpen the tuning specificity of classes of M/TCs to odors during sensory processing.

Mismatch novelty exploration training shifts VPAC1 receptor-mediated modulation of hippocampal synaptic plasticity by endogenous VIP in male rats.

Novelty influences hippocampal-dependent memory through metaplasticity. Mismatch novelty detection activates the human hippocampal CA1 area and enhances rat hippocampal-dependent learning and exploration. Remarkably, mismatch novelty training (NT) also enhances rodent hippocampal synaptic plasticity while inhibition of VIP interneurons promotes rodent exploration. Since VIP, acting on VPAC1 receptors (Rs), restrains hippocampal LTP and depotentiation by modulating disinhibition, we now investigated the impact of NT on VPAC1 modulation of hippocampal synaptic plasticity in male Wistar rats. NT enhanced both CA1 hippocampal LTP and depotentiation unlike exploring an empty holeboard (HT) or a fixed configuration of objects (FT). Blocking VIP VPAC1Rs with PG 97269 (100 nM) enhanced both LTP and depotentiation in naïve animals, but this effect was less effective in NT rats. Altered endogenous VIP modulation of LTP was absent in animals exposed to the empty environment (HT). HT and FT animals showed mildly enhanced synaptic VPAC1R levels, but neither VIP nor VPAC1R levels were altered in NT animals. Conversely, NT enhanced the GluA1/GluA2 AMPAR ratio and gephyrin synaptic content but not PSD-95 excitatory synaptic marker. In conclusion, NT influences hippocampal synaptic plasticity by reshaping brain circuits modulating disinhibition and its control by VIP-expressing hippocampal interneurons while upregulation of VIP VPAC1Rs is associated with the maintenance of VIP control of LTP in FT and HT animals. This suggests VIP receptor ligands may be relevant to co-adjuvate cognitive recovery therapies in aging or epilepsy, where LTP/LTD imbalance occurs.

Pathomechanisms of behavioral abnormalities in Huntington disease: an update.

Huntington disease (HD), a devastating autosomal-dominant neurodegenerative disease caused by an expanded CAG trinucleotide repeat, is clinically characterized by a triad of symptoms including involuntary motions, behavior problems and cognitive deficits. Behavioral symptoms with anxiety, irritability, obsessive-compulsive behaviors, apathy and other neuropsychiatric symptoms, occurring in over 50% of HD patients are important features of this disease and contribute to impairment of quality of life, but their pathophysiology is poorly understood. Behavior problems, more frequent than depression, can be manifest before obvious motor symptoms and occur across all HD stages, usually correlated with duration of illness. While specific neuropathological data are missing, the relations between gene expression and behavior have been elucidated in transgenic models of HD. Disruption of interneuronal communications, with involvement of prefronto-striato-thalamic networks and hippocampal dysfunctions produce deficits in multiple behavioral domains. These changes that have been confirmed by multistructural neuroimaging studies are due to a causal cascade linking molecular pathologies (glutamate-mediated excitotoxicity, mitochondrial dysfunctions inducing multiple biochemical and structural alterations) and deficits in multiple behavioral domains. The disruption of large-scale connectivities may explain the variability of behavior profiles and is useful in understanding the biological backgrounds of functional decline in HD. Such findings offer new avenues for targeted treatments in terms of minimizing neurobehavioral impairment in HD.

Localized chemogenetic silencing of inhibitory neurons: a novel mouse model of focal cortical epileptic activity.

Focal cortical epilepsies are frequently refractory to available anticonvulsant drug therapies. One key factor contributing to this state is the limited availability of animal models that allow to reliably study focal cortical seizures and how they recruit surrounding brain areas in vivo. In this study, we selectively expressed the inhibitory chemogenetic receptor, hM4D, in GABAergic neurons in focal cortical areas using viral gene transfer. GABAergic silencing using Clozapine-N-Oxide (CNO) demonstrated reliable induction of local epileptiform events in the electroencephalogram signal of awake freely moving mice. Anesthetized mice experiments showed consistent induction of focal epileptiform-events in both the barrel cortex (BC) and the medial prefrontal cortex (mPFC), accompanied by high-frequency oscillations, a known characteristic of human seizures. Epileptiform-events showed propagation indication with favored propagation pathways: from the BC on 1 hemisphere to its counterpart and from the BC to the mPFC, but not vice-versa. Lastly, sensory whisker-pad stimulation evoked BC epileptiform events post-CNO, highlighting the potential use of this model in studying sensory-evoked seizures. Combined, our results show that targeted chemogenetic inhibition of GABAergic neurons using hM4D can serve as a novel, versatile, and reliable model of focal cortical epileptic activity suitable for systematically studying cortical ictogenesis in different cortical areas.

Neuropsychiatric symptoms and white matter hyperintensities in older adults without dementia.

OBJECTIVE: We aimed to examine associations between neuropsychiatric symptoms (NPS) and white matter hyperintensities (WMH) status in older adults without dementia under the hypothesis that WMH increased the odds of having NPS. DESIGN: Longitudinal analysis of data acquired from the National Alzheimer's Coordinating Center Uniform Data Set. SETTINGS: Data were derived from 46 National Institute on Aging - funded Alzheimer's Disease Research Centers. PARTICIPANTS: NACC participants aged ≥50 years with available data on WMH severity with a diagnosis of mild cognitive impairment (MCI) or who were cognitively unimpaired (CU) were studied. Among 4617 CU participants, 376 had moderate and 54 extensive WMH. Among 3170 participants with MCI, 471 had moderate and 88 had extensive WMH. MEASUREMENTS: Using Cardiovascular Health Study (CHS) scores, WMH were coded as no to mild (CHS score: 0-4), moderate (score: 5-6) or extensive (score: 7-8). NPS were quantified on the Neuropsychiatric Inventory Questionnaire. Binary logistic regression models estimated the odds of reporting each of 12 NPS by WMH status separately for individuals with MCI or who were CU. RESULTS: Compared to CU individuals with no to mild WMH, the odds of having elation [9.87, (2.63-37.10)], disinhibition [4.42, (1.28-15.32)], agitation [3.51, (1.29-9.54)] or anxiety [2.74, (1.28-5.88)] were higher for the extensive WMH group, whereas the odds of having disinhibition were higher for the moderate WMH group [1.94, (1.05-3.61)]. In the MCI group, he odds of NPS did not vary by WMH status. CONCLUSIONS: Extensive WMH were associated with higher odds of NPS in CU older adults but not in those with MCI.

Differences in dietary acceptability, restraint, disinhibition, and hunger among African American participants randomized to either a vegan or omnivorous soul food diet.

The Nutritious Eating with Soul study was a 24-month, randomized behavioral nutrition intervention among African American adults. This present study, which is a secondary analysis of the NEW Soul study, examined changes in dietary acceptability, restraint, disinhibition, and hunger. Participants (n = 159; 79% female, 74% with ≥ college degree, mean age 48.4 y) were randomized to either a soul food vegan (n = 77) or soul food omnivorous (n = 82) diet and participated in a two-year behavioral nutrition intervention. Questionnaires assessing dietary acceptability (Food Acceptability Questionnaire; FAQ) and dietary restraint, disinhibition, and hunger (Three-Factor Eating Questionnaire; TFEQ) were completed at baseline, 3, 6, 12, and 24 months. Mixed models were specified with main effects (group and time) and interaction effects (group by time) to estimate mean differences in FAQ and TFEQ scores using intent-to-treat analysis. After adjusting for employment, education, food security status, sex, and age, there were no differences in any of the FAQ items, total FAQ score, dietary restraint, disinhibition, and hunger at any timepoint except for one item of the FAQ at 12 months. Participants in the vegan group reported a greater increase in satisfaction after eating a meal than the omnivorous group (mean difference 0.80 ± 0.32, 95% CI 0.18, 1.42; P = 0.01). This is one of the first studies to examine differences in dietary acceptability, hunger, and other eating factors among African American adults randomized to either a vegan or omnivorous soul food diet. The findings highlight that plant-based eating styles are equally acceptable to omnivorous eating patterns and have similar changes in hunger, restraint, and disinhibition. These results suggest that plant-based eating styles can be an acceptable dietary pattern to recommend for cardiovascular disease prevention and may result in greater post-meal satisfaction.

All-or-none disconnection of pyramidal inputs onto parvalbumin-positive interneurons gates ocular dominance plasticity.

Disinhibition is an obligatory initial step in the remodeling of cortical circuits by sensory experience. Our investigation on disinhibitory mechanisms in the classical model of ocular dominance plasticity uncovered an unexpected form of experience-dependent circuit plasticity. In the layer 2/3 of mouse visual cortex, monocular deprivation triggers a complete, "all-or-none," elimination of connections from pyramidal cells onto nearby parvalbumin-positive interneurons (Pyr→PV). This binary form of circuit plasticity is unique, as it is transient, local, and discrete. It lasts only 1 d, and it does not manifest as widespread changes in synaptic strength; rather, only about half of local connections are lost, and the remaining ones are not affected in strength. Mechanistically, the deprivation-induced loss of Pyr→PV is contingent on a reduction of the protein neuropentraxin2. Functionally, the loss of Pyr→PV is absolutely necessary for ocular dominance plasticity, a canonical model of deprivation-induced model of cortical remodeling. We surmise, therefore, that this all-or-none loss of local Pyr→PV circuitry gates experience-dependent cortical plasticity.

Basal forebrain mediates prosocial behavior via disinhibition of midbrain dopamine neurons.

Sociability is fundamental for our daily life and is compromised in major neuropsychiatric disorders. However, the neuronal circuit mechanisms underlying prosocial behavior are still elusive. Here we identify a causal role of the basal forebrain (BF) in the control of prosocial behavior via inhibitory projections that disinhibit the midbrain ventral tegmental area (VTA) dopamine (DA) neurons. Specifically, BF somatostatin-positive (SST) inhibitory neurons were robustly activated during social interaction. Optogenetic inhibition of these neurons in BF or their axon terminals in the VTA largely abolished social preference. Electrophysiological examinations further revealed that SST neurons predominantly targeted VTA GABA neurons rather than DA neurons. Consistently, optical inhibition of SST neuron axon terminals in the VTA decreased DA release in the nucleus accumbens during social interaction, confirming a disinhibitory action. These data reveal a previously unappreciated function of the BF in prosocial behavior through a disinhibitory circuitry connected to the brain's reward system.

Disinhibition Is an Essential Network Motif Coordinated by GABA Levels and GABA B Receptors.

Network dynamics are crucial for action and sensation. Changes in synaptic physiology lead to the reorganization of local microcircuits. Consequently, the functional state of the network impacts the output signal depending on the firing patterns of its units. Networks exhibit steady states in which neurons show various activities, producing many networks with diverse properties. Transitions between network states determine the output signal generated and its functional results. The temporal dynamics of excitation/inhibition allow a shift between states in an operational network. Therefore, a process capable of modulating the dynamics of excitation/inhibition may be functionally important. This process is known as disinhibition. In this review, we describe the effect of GABA levels and GABAB receptors on tonic inhibition, which causes changes (due to disinhibition) in network dynamics, leading to synchronous functional oscillations.

Toxic sensation seeking? Psychological distress, cyberbullying, and the moderating effect of online disinhibition among adults.

Cyberbullying among adults is barely studied, though its consequences may be as severe as in children and adolescents. The present study investigated the links between psychological distress, cyber-perpetration, and passive cyber-bystander behavior. We also explored the moderating role of toxic disinhibition in this regard. Our sample comprised 385 adults aged 19-66 (M = 28.35, SD = 11.22, 76.62% females). The results suggested that psychological distress was significantly associated with cyberbullying perpetration and passive bystander behavior. Also, higher psychological distress significantly predicted toxic disinhibition. Further moderation analyses suggested that at high and medium levels of toxic disinhibition, psychological distress significantly predicted cyberbullying perpetration but not passive cyber-bystander behavior. Finally, we discuss our results regarding their theoretical and practical implication for cyberbullying prevention among adults.

Selective Inhibitory Circuit Dysfunction after Chronic Frontal Lobe Contusion.

Traumatic brain injury (TBI) is a leading cause of neurologic disability; the most common deficits affect prefrontal cortex-dependent functions such as attention, working memory, social behavior, and mental flexibility. Despite this prevalence, little is known about the pathophysiology that develops in frontal cortical microcircuits after TBI. We investigated whether alterations in subtype-specific inhibitory circuits are associated with cognitive inflexibility in a mouse model of frontal lobe contusion in both male and female mice that recapitulates aberrant mental flexibility as measured by deficits in rule reversal learning. Using patch-clamp recordings and optogenetic stimulation, we identified selective vulnerability in the non-fast-spiking and somatostatin-expressing (SOM+) subtypes of inhibitory neurons in layer V of the orbitofrontal cortex 2 months after injury. These subtypes exhibited reduced intrinsic excitability and a decrease in their synaptic output onto pyramidal neurons, respectively. By contrast, the fast-spiking and parvalbumin-expressing interneurons did not show changes in intrinsic excitability or synaptic output, respectively. Impairments in non-fast-spiking/SOM+ inhibitory circuit function were also associated with network hyperexcitability. These findings provide evidence for selective disruptions within specific inhibitory microcircuits that may guide the development of novel therapeutics for TBI.SIGNIFICANCE STATEMENT TBI frequently leads to chronic deficits in cognitive and behavioral functions that involve the prefrontal cortex, yet the maladaptive changes that occur in these cortical microcircuits are unknown. Our data indicate that alterations in subtype-specific inhibitory circuits, specifically vulnerability in the non-fast-spiking/somatostatin-expressing interneurons, occurs in the orbitofrontal cortex in the context of chronic deficits in reversal learning. These neurons exhibit reduced excitability and synaptic output, whereas the other prominent inhibitory population in layer V, the fast-spiking/parvalbumin-expressing interneurons as well as pyramidal neurons are not affected. Our work offers mechanistic insight into the subtype-specific function of neurons that may contribute to mental inflexibility after TBI.