Neurons In Prefrontal Cortex Research Articles

Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications.

Prefrontal cortex (PFC) serves as the chief executive officer of the brain, controlling the highest level cognitive and emotional processes. Its local circuits among glutamatergic principal neurons and GABAergic interneurons, as well as its long-range connections with other brain regions, have been functionally linked to specific behaviors, ranging from working memory to reward seeking. The efficacy of synaptic signaling in PFC network is profundedly influenced by monoaminergic inputs via the activation of dopamine, adrenergic or serotonin receptors. Stress hormones and neuropeptides also exert complex effects on the synaptic structure and function of PFC neurons. Dysregulation of PFC synaptic transmission is strongly linked to the social deficits, affective disturbance, and memory loss in brain disorders including autism, schizophrenia, depression and Alzheimer’s disease. Critical neural circuits, biological pathways, and molecular players that go awry in these mental illnesses have been revealed by integrated electrophysiological, optogenetic, biochemical, and transcriptomic studies of PFC. Novel epigenetic mechanism-based strategies are proposed as potential avenues of therapeutic intervention for PFC-involved diseases. This review provides an overview on PFC network organization and synaptic modulation, as well as the mechanisms linking PFC dysfunction to the pathophysiology of neurodevelopmental, neuropsychiatric and neurodegenerative diseases. Insights from the preclinical studies offer the potential for discovering new medical treatment of human patients with these brain disorders.

Prefrontal deep projection neurons enable cognitive flexibility via persistent feedback monitoring

Cognitive flexibility, the ability to alter strategy according to changing stimulus-response-reward relationships, is critical for updating learned behavior. Attentional set-shifting, a test of cognitive flexibility, depends on the activity of prefrontal cortex (PFC). It remains unclear, however, what role PFC neurons play to support set-shifting. Using optogenetics and two-photon calcium imaging, we demonstrate that medial PFC activity does not bias sensorimotor responses during set-shifting, but rather enables set-shifting by encoding trial feedback information, a role it has been known to play in other contexts. Unexpectedly, the functional properties of PFC cells did not vary with their efferent projection targets. Instead, representations of trial feedback formed a topological gradient, with cells more strongly selective for feedback information located further from the pial surface, where afferent input from the anterior cingulate cortex was denser. These findings identify a critical role for deep PFC projection neurons in enabling set-shifting through behavioral feedback monitoring.

Altered Relationship Between Parvalbumin and Perineuronal Nets in an Autism Model.

Altered function or presence of inhibitory neurons is documented in autism spectrum disorders (ASD), but the mechanism underlying this alternation is poorly understood. One major subtype of inhibitory neurons altered is the parvalbumin (PV)-containing neurons with reduced density and intensity in ASD patients and model mice. A subpopulation of PV+ neurons expresses perineuronal nets (PNN). To better understand whether the relationship between PV and PNN is altered in ASD, we measured quantitatively the intensities of PV and PNN in single PV+ neurons in the prelimbic prefrontal cortex (PrL-PFC) of a valproic acid (VPA) model of ASD at different ages. We found a decreased PV intensity but increased PNN intensity in VPA mice. The relationship between PV and PNN intensities is altered in VPA mice, likely due to an “abnormal” subpopulation of neurons with an altered PV-PNN relationship. Furthermore, reducing PNN level using in vivo injection of chondroitinase ABC corrects the PV expression in adult VPA mice. We suggest that the interaction between PV and PNN is disrupted in PV+ neurons in VPA mice which may contribute to the pathology in ASD.

Cocaine Reduces the Neuronal Population While Upregulating Dopamine D2-Receptor-Expressing Neurons in Brain Reward Regions: Sex-Effects

Addiction to cocaine is associated with dysfunction of the dopamine mesocortical system including impaired dopamine-2 receptor (D2r) signaling. However, the effects of chronic cocaine on neuronal adaptations in this system have not been systematically examined and data available is mostly from males. Here, we investigated changes in the total neuronal density and relative concentration of D2r-expressing neurons in the medial prefrontal cortex (mPFC), dorsal striatum (Dstr), nucleus accumbens (NAc), and ventral tegmental area (VTA) in both male and female mice passively exposed to cocaine for two weeks. In parallel experiments, we measured mRNA levels for Drd2 and for opioid peptides (mPenk and mPdyn). Through a combination of large field of view fluorescent imaging with BAC transgenic D2r-eGFP mice and immunostaining, we observed that cocaine exposed mice had a higher density of D2r-positive cells that was most prominent in mPFC and VTA and larger for females than for males. This occurred amidst an overall significant decrease in neuronal density (measured with NeuN) in both sexes. However, increases in Drd2 mRNA levels with cocaine were only observed in mPFC and Dstr in females, which might reflect the limited sensitivity of the method. Our findings, which contrast with previous findings of cocaine-induced downregulation of D2r binding availability, could reflect a phenotypic shift in neurons that did not previously express Drd2 and merits further investigation. Additionally, the neuronal loss particularly in mPFC with chronic cocaine might contribute to the cognitive impairments observed with cocaine use disorder.

Age-related calcium dysregulation linked with tau pathology and impaired cognition in non-human primates.

IntroductionThe etiology of sporadic Alzheimer's disease (AD) requires non‐genetically modified animal models.MethodsThe relationship of tau phosphorylation to calcium‐cyclic adenosine monophosphate (cAMP)‐protein kinase A (PKA) dysregulation was analyzed in aging rhesus macaque dorsolateral prefrontal cortex (dlPFC) and rat primary cortical neurons using biochemistry and immuno‐electron microscopy. The influence of calcium leak from ryanodine receptors (RyRs) on neuronal firing and cognitive performance was examined in aged macaques.ResultsAged monkeys naturally develop hyperphosphorylated tau, including AD biomarkers (AT8 (pS202/pT205) and pT217) and early tau pathology markers (pS214 and pS356) that correlated with evidence of increased calcium leak (pS2808‐RyR2). Calcium also regulated early tau phosphorylation in vitro. Age‐related reductions in the calcium‐binding protein, calbindin, and in phosphodiesterase PDE4D were seen within dlPFC pyramidal cell dendrites. Blocking RyRs with S107 improved neuronal firing and cognitive performance in aged macaques.DiscussionDysregulated calcium signaling confers risk for tau pathology and provides a potential therapeutic target.

Slower prefrontal metastable dynamics during deliberation predicts error trials in a distance discrimination task

SUMMARYCortical activity related to erroneous behavior in discrimination or decision-making tasks is rarely analyzed, yet it can help clarify which computations are essential during a specific task. Here, we use a hidden Markov model (HMM) to perform a trial-by-trial analysis of the ensemble activity of dorsolateral prefrontal cortex (PFdl) neurons of rhesus monkeys performing a distance discrimination task. By segmenting the neural activity into sequences of metastable states, HMM allows us to uncover modulations of the neural dynamics related to internal computations. We find that metastable dynamics slow down during error trials, while state transitions at a pivotal point during the trial take longer in difficult correct trials. Both these phenomena occur during the decision interval, with errors occurring in both easy and difficult trials. Our results provide further support for the emerging role of metastable cortical dynamics in mediating complex cognitive functions and behavior.

Bi-directional regulation of cognitive control by distinct prefrontal cortical output neurons to thalamus and striatum

The medial prefrontal cortex (mPFC) steers goal-directed actions and withholds inappropriate behavior. Dorsal and ventral mPFC (dmPFC/vmPFC) circuits have distinct roles in cognitive control, but underlying mechanisms are poorly understood. Here we use neuroanatomical tracing techniques, in vitro electrophysiology, chemogenetics and fiber photometry in rats engaged in a 5-choice serial reaction time task to characterize dmPFC and vmPFC outputs to distinct thalamic and striatal subdomains. We identify four spatially segregated projection neuron populations in the mPFC. Using fiber photometry we show that these projections distinctly encode behavior. Postsynaptic striatal and thalamic neurons differentially process synaptic inputs from dmPFC and vmPFC, highlighting mechanisms that potentially amplify distinct pathways underlying cognitive control of behavior. Chemogenetic silencing of dmPFC and vmPFC projections to lateral and medial mediodorsal thalamus subregions oppositely regulate cognitive control. In addition, dmPFC neurons projecting to striatum and thalamus divergently regulate cognitive control. Collectively, we show that mPFC output pathways targeting anatomically and functionally distinct striatal and thalamic subregions encode bi-directional command of cognitive control.

PTEN in prefrontal cortex is essential in regulating depression-like behaviors in mice

Chronic stress is an environmental risk factor for depression and causes neuronal atrophy in the prefrontal cortex (PFC) and other brain regions. It is still unclear about the molecular mechanism underlying the behavioral alterations and neuronal atrophy induced by chronic stress. We here report that phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a mediator for chronic stress-induced depression-like behaviors and neuronal atrophy in mice. One-month chronic restraint stress (CRS) up-regulated PTEN signaling pathway in the PFC of mice as indicated by increasing levels of PTEN, p-MEK, and p-ERK but decreasing levels of p-AKT. Over-expression of Pten in the PFC led to an increase of depression-like behaviors, whereas genetic inactivation or knockdown of Pten in the PFC prevented the CRS-induced depression-like behaviors. In addition, systemic administration of PTEN inhibitor was also able to prevent these behaviors. Cellular examination showed that Pten over-expression or the CRS treatment resulted in PFC neuron atrophy, and this atrophy was blocked by genetic inactivation of Pten or systemic administration of PTEN inhibitor. Furthermore, possible causal link between Pten and glucocorticoids was examined. In chronic dexamethasone (Dex, a glucocorticoid agonist) treatment-induced depression model, increased PTEN levels were observed, and depression-like behaviors and PFC neuron atrophy were attenuated by the administration of PTEN inhibitor. Our results indicate that PTEN serves as a key mediator in chronic stress-induced neuron atrophy as well as depression-like behaviors, providing molecular evidence supporting the synaptic plasticity theory of depression.

Single-cell morphological characterization of CRH neurons throughout the whole mouse brain

BackgroundCorticotropin-releasing hormone (CRH) is an important neuromodulator that is widely distributed in the brain and plays a key role in mediating stress responses and autonomic functions. While the distribution pattern of fluorescently labeled CRH-expressing neurons has been studied in different transgenic mouse lines, a full appreciation of the broad diversity of this population and local neural connectivity can only come from integration of single-cell morphological information as a defining feature. However, the morphologies of single CRH neurons and the local circuits formed by these neurons have not been acquired at brain-wide and dendritic-scale levels.ResultsWe screened the EYFP-expressing CRH-IRES-Cre;Ai32 mouse line to reveal the morphologies of individual CRH neurons throughout the whole mouse brain by using a fluorescence micro-optical sectioning tomography (fMOST) system. Diverse dendritic morphologies and projection fibers of CRH neurons were found in various brain regions. Follow-up reconstructions showed that hypothalamic CRH neurons had the smallest somatic volumes and simplest dendritic branches and that CRH neurons in several brain regions shared a common bipolar morphology. Further investigations of local CRH neurons in the medial prefrontal cortex unveiled somatic depth-dependent morphologies of CRH neurons that exhibited three types of mutual connections: basal dendrites (upper layer) with apical dendrites (layer 3); dendritic-somatic connections (in layer 2/3); and dendritic-dendritic connections (in layer 4). Moreover, hypothalamic CRH neurons were classified into two types according to their somatic locations and characteristics of dendritic varicosities. Rostral-projecting CRH neurons in the anterior parvicellular area had fewer and smaller dendritic varicosities, whereas CRH neurons in the periventricular area had more and larger varicosities that were present within dendrites projecting to the third ventricle. Arborization-dependent dendritic spines of CRH neurons were detected, among which the most sophisticated types were found in the amygdala and the simplest types were found in the hypothalamus.ConclusionsBy using the CRH-IRES-Cre;Ai32 mouse line and fMOST imaging, we obtained region-specific morphological distributions of CRH neurons at the dendrite level in the whole mouse brain. Taken together, our findings provide comprehensive brain-wide morphological information of stress-related CRH neurons and may facilitate further studies of the CRH neuronal system.

Repeated victorious and defeat experiences induce similar apical dendritic spine remodeling in CA1 hippocampus of rats

In this study, apical dendritic spine density of neurons in hippocampal, amygdalar and prefrontal cortical areas was compared in rats that were repeatedly winning or losing social conflicts. Territorial male wild-type Groningen (WTG) rats were allowed multiple daily attacks (>20 times) on intruder males in the resident-intruder paradigm. Frequent winning experiences are known to facilitate uncontrolled aggressive behavior reflected in aggressive attacks on anesthetized males which was also observed in the winners in this study. Both winners and losers were socially housed during the experiments; winners with females to stimulate territorial behavior, and losers with two other losing male rats. Twenty-four hours after the last social encounter, brains from experienced residential winners and repeatedly defeated intruder rats were collected and neuronal morphology in selected brain regions was studied via Golgi-Cox staining. Results indicate that spine density in the apical dendrites of the hippocampal CA1 reduced similarly in both winners and losers. In addition, winners showed increased spine densities at the proximal segments (20−30 μm) of the basolateral amygdala neurons and losers tended to show a decreased spine density at the more proximal segments of the infralimbic region of prefrontal cortex neurons. No effect of winning and losing was observed in the medial amygdala. The atrophic effect of repeated defeats in hippocampal and prefrontal regions was anticipated despite the fact that social housing of the repeatedly losing intruder males may have played a protective role. The reduction of hippocampal spine density in the winners seems surprising but supports previous findings in hierarchical dominant males in rat colonies. The dominants showed even greater shrinkage of the apical dendritic arbors of hippocampal CA3 pyramidal neurons compared to the stressed subordinates.

A transient developmental increase in prefrontal activity alters network maturation and causes cognitive dysfunction in adult mice

SummaryDisturbed neuronal activity in neuropsychiatric pathologies emerges during development and might cause multifold neuronal dysfunction by interfering with apoptosis, dendritic growth, and synapse formation. However, how altered electrical activity early in life affects neuronal function and behavior in adults is unknown. Here, we address this question by transiently increasing the coordinated activity of layer 2/3 pyramidal neurons in the medial prefrontal cortex of neonatal mice and monitoring long-term functional and behavioral consequences. We show that increased activity during early development causes premature maturation of pyramidal neurons and affects interneuronal density. Consequently, altered inhibitory feedback by fast-spiking interneurons and excitation/inhibition imbalance in prefrontal circuits of young adults result in weaker evoked synchronization of gamma frequency. These structural and functional changes ultimately lead to poorer mnemonic and social abilities. Thus, prefrontal activity during early development actively controls the cognitive performance of adults and might be critical for cognitive symptoms in neuropsychiatric diseases.

Lysergic acid diethylamide differentially modulates the reticular thalamus, mediodorsal thalamus, and infralimbic prefrontal cortex: An in vivo electrophysiology study in male mice.

Background:The reticular thalamus gates thalamocortical information flow via finely tuned inhibition of thalamocortical cells in the mediodorsal thalamus. Brain imaging studies in humans show that the psychedelic lysergic acid diethylamide (LSD) modulates activity and connectivity within the cortico-striato-thalamo-cortical (CSTC) circuit, altering consciousness. However, the electrophysiological effects of LSD on the neurons in these brain areas remain elusive.Methods:We employed in vivo extracellular single-unit recordings in anesthetized adult male mice to investigate the dose–response effects of cumulative LSD doses (5–160 µg/kg, intraperitoneal) upon reticular thalamus GABAergic neurons, thalamocortical relay neurons of the mediodorsal thalamus, and pyramidal neurons of the infralimbic prefrontal cortex.Results:LSD decreased spontaneous firing and burst-firing activity in 50% of the recorded reticular thalamus neurons in a dose–response fashion starting at 10 µg/kg. Another population of neurons (50%) increased firing and burst-firing activity starting at 40 µg/kg. This modulation was accompanied by an increase in firing and burst-firing activity of thalamocortical neurons in the mediodorsal thalamus. On the contrary, LSD excited infralimbic prefrontal cortex pyramidal neurons only at the highest dose tested (160 µg/kg). The dopamine D2 receptor (D2) antagonist haloperidol administered after LSD increased burst-firing activity in the reticular thalamus neurons inhibited by LSD, decreased firing and burst-firing activity in the mediodorsal thalamus, and showed a trend towards further increasing the firing activity of neurons of the infralimbic prefrontal cortex.Conclusion:LSD modulates firing and burst-firing activity of reticular thalamus neurons and disinhibits mediodorsal thalamus relay neurons at least partially in a D2-mediated fashion. These effects of LSD on thalamocortical gating could explain its consciousness-altering effects in humans.

Neural circuits and activity dynamics underlying sex-specific effects of chronic social isolation stress

Exposure to prolonged stress in critical developmental periods induces heightened vulnerability to psychiatric disorders, which may have sex-specific consequences. Here we investigate the neuronal circuits mediating behavioral changes in mice after chronic adolescent social isolation stress. Escalated aggression is exhibited in stressed males, while social withdrawal is shown in stressed females. Invivo multichannel recordings of free-moving animals indicate that pyramidal neurons in prefrontal cortex (PFC) from stressed males exhibit the significantly decreased spike activity during aggressive attacks, while PFC pyramidal neurons from stressed females show a blunted increase of discharge rates during sociability tests. Chemogenetic and electrophysiological evidence shows that PFC hypofunctioning and BLA principal neuron hyperactivity contribute to the elevated aggression in stressed males, while PFC hypofunctioning and VTA dopamine neuron hypoactivity contribute to the diminished sociability in stressed females. These results establish a framework for understanding the circuit and physiological mechanisms underlying sex-specific divergent effects of stress.

Role of Medial Prefrontal Cortical Neurons and Oxytocin Modulation in the Establishment of Social Buffering.

Fear-related behaviors are rigidly controlled by the medial prefrontal cortex (mPFC). The mPFC is activated by the prosocial hormone oxytocin, which plays an important role in social buffering. We used a slice patch current-clamp recording in single- and pair-exposed rats who were subjected to electric shocks, to determine the cellular mechanism of the action of oxytocin in the mPFC under social buffering conditions. Pair-exposed rats showed a significant reduction in both freezing and passive avoidance behaviors compared to single-exposed rats. It was observed that input resistance in pyramidal neurons decreased in both single- and pair-exposed rats than na?ve rats, but input resistance in interneurons increased in pair-exposed rats than single-exposed rats. We found that the number of action potential (AP) spikes in the mPFC pyramidal neurons decreased significantly in pair-exposed rats than in single-exposed rats. The pyramidal neurons in the mPFC were similarly regulated by oxytocin in singleand pair-exposed rats, while the number of AP spikes in interneurons by oxytocin decreased in single-exposed rats, but there was no significant change in pair-exposed rats. Therefore, our findings reveal that a decrease in mPFC pyramidal neuronal activity in pair-exposed rats through social interaction induces a reduction in fear-related behavior via obstruction of fear-memory formation; however, no such reduction was observed in single-exposed rats. Moreover, we suggest that the oxytocin-mediated decrease in neuronal activity in the mPFC could facilitate social buffering.

Neuregulin signaling mediates the acute and sustained antidepressant effects of subanesthetic ketamine

Subanesthetic ketamine evokes rapid antidepressant effects in human patients that persist long past ketamine’s chemical half-life of ~2 h. Ketamine’s sustained antidepressant action may be due to modulation of cortical plasticity. We find that ketamine ameliorates depression-like behavior in the forced swim test in adult mice, and this depends on parvalbumin-expressing (PV) neuron-directed neuregulin-1 (NRG1)/ErbB4 signaling. Ketamine rapidly downregulates NRG1 expression in PV inhibitory neurons in mouse medial prefrontal cortex (mPFC) following a single low-dose ketamine treatment. This NRG1 downregulation in PV neurons co-tracks with the decreases in synaptic inhibition to mPFC excitatory neurons for up to a week. This results from reduced synaptic excitation to PV neurons, and is blocked by exogenous NRG1 as well as by PV targeted ErbB4 receptor knockout. Thus, we conceptualize that ketamine’s effects are mediated through rapid and sustained cortical disinhibition via PV-specific NRG1 signaling. Our findings reveal a novel neural plasticity-based mechanism for ketamine’s acute and long-lasting antidepressant effects.

Oral application of clozapine-N-oxide using the micropipette-guided drug administration (MDA) method in mouse DREADD systems.

The designer receptor exclusively activated by designer drugs (DREADD) system is one of the most widely used chemogenetic techniques to modulate the activity of cell populations in the brains of behaving animals. DREADDs are activated by acute or chronic administration of their ligand, clozapine-N-oxide (CNO). There is, however, a current lack of a non-invasive CNO administration technique that can control for drug timing and dosing without inducing substantial distress for the animals. Here, we evaluated whether the recently developed micropipette-guided drug administration (MDA) method, which has been used as a non-invasive and minimally stressful alternative to oral gavages, may be applied to administer CNO orally to activate DREADDs in a dosing- and timing-controlled manner. Unlike standard intraperitoneal injections, administration of vehicle substances via MDA did not elevate plasma levels of the major stress hormone, corticosterone, and did not attenuate exploratory activity in the open field test. At the same time, however, administration of CNO via MDA or intraperitoneally was equally efficient in activating hM3DGq-expressing neurons in the medial prefrontal cortex, as evident by time-dependent increases in mRNA levels of neuronal immediate early genes (cFos, Arc and Zif268) and cFos-immunoreactive neurons. Compared to vehicle given via MDA, oral administration of CNO via MDA was also found to potently increase locomotor activity in mice that express hM3DGq in prefrontal neurons. Taken together, our study confirms the effectiveness of CNO given orally via MDA and provides a novel method for non-stressful, yet well controllable CNO treatments in mouse DREADD systems.

Distinct Spiking Patterns of Excitatory and Inhibitory Neurons and LFP Oscillations in Prefrontal Cortex During Sensory Discrimination.

Prefrontal cortex (PFC) are broadly linked to various aspects of behavior. During sensory discrimination, PFC neurons can encode a range of task related information, including the identity of sensory stimuli and related behavioral outcome. However, it remains largely unclear how different neuron subtypes and local field potential (LFP) oscillation features in the mouse PFC are modulated during sensory discrimination. To understand how excitatory and inhibitory PFC neurons are selectively engaged during sensory discrimination and how their activity relates to LFP oscillations, we used tetrode recordings to probe well-isolated individual neurons, and LFP oscillations, in mice performing a three-choice auditory discrimination task. We found that a majority of PFC neurons, 78% of the 711 recorded individual neurons, exhibited sensory discrimination related responses that are context and task dependent. Using spike waveforms, we classified these responsive neurons into putative excitatory neurons with broad waveforms or putative inhibitory neurons with narrow waveforms, and found that both neuron subtypes were transiently modulated, with individual neurons’ responses peaking throughout the entire duration of the trial. While the number of responsive excitatory neurons remain largely constant throughout the trial, an increasing fraction of inhibitory neurons were gradually recruited as the trial progressed. Further examination of the coherence between individual neurons and LFPs revealed that inhibitory neurons exhibit higher spike-field coherence with LFP oscillations than excitatory neurons during all aspects of the trial and across multiple frequency bands. Together, our results demonstrate that PFC excitatory neurons are continuously engaged during sensory discrimination, whereas PFC inhibitory neurons are increasingly recruited as the trial progresses and preferentially coordinated with LFP oscillations. These results demonstrate increasing involvement of inhibitory neurons in shaping the overall PFC dynamics toward the completion of the sensory discrimination task.

Increased Synaptic Strength and mGlu2/3 Receptor Plasticity on Mouse Prefrontal Cortex Intratelencephalic Pyramidal Cells Following Intermittent Access to Ethanol.

The medial prefrontal cortex (PFC) is crucial for regulating craving and alcohol seeking in alcohol use disorder (AUD) patients and alcohol seeking in animal models. Maladaptive changes in volitional ethanol (EtOH) intake have been associated with PFC function, yet synaptic adaptations within PFC have not been consistently detected in voluntary drinking rodent models. At least 80% of the neurons in PFC are glutamatergic pyramidal cells. Pyramidal cells provide the predominant cortical output to several brain regions relevant to AUD, including structures within the telencephalon (IT: e.g., basal ganglia, amygdala, other neocortical regions) and outside the telencephalon (ET: e.g., lateral hypothalamus, midbrain monoaminergic structures, thalamus). In addition to their anatomical distinctions, studies from several laboratories have revealed that prefrontal cortical IT and ET pyramidal cells may be differentiated by specific electrophysiological parameters. These distinguishable parameters make it possible to readily classify pyramidal cells into separable subtypes. Here, we employed and validated the hyperpolarization sag ratio as a diagnostic proxy for separating ET (type A) and IT (type B) neurons. We recorded from deep-layer prelimbic PFC pyramidal cells of mice 1day after 4 to 5weeks of intermittent access (IA) EtOH exposure. Membrane properties were not altered by IA EtOH, but excitatory postsynaptic strength onto IT type B neurons was selectively enhanced in slices from IA EtOH mice. The increased excitatory drive was accompanied by enhanced mGlu2/3 receptor plasticity on IT type B neurons, providing a potential translational approach to mitigate cognitive and motivational changes to PFC function related to binge drinking. Together, these studies provide insight into the specific PFC neurocircuits altered by voluntary drinking. In addition, the findings provide an additional rationale for developing compounds that potentiate mGlu2 and/or mGlu3 receptor function as potential treatments for AUD.

Distinct neural networks for the volitional control of vocal and manual actions in the monkey homologue of Broca's area.

The ventrolateral frontal lobe (Broca's area) of the human brain is crucial in speech production. In macaques, neurons in the ventrolateral prefrontal cortex, the suggested monkey homologue of Broca's area, signal the volitional initiation of vocalizations. We explored whether this brain area became specialized for vocal initiation during primate evolution and trained macaques to alternate between a vocal and manual action in response to arbitrary cues. During task performance, single neurons recorded from the ventrolateral prefrontal cortex and the rostroventral premotor cortex of the inferior frontal cortex predominantly signaled the impending vocal or, to a lesser extent, manual action, but not both. Neuronal activity was specific for volitional action plans and differed during spontaneous movement preparations. This implies that the primate inferior frontal cortex controls the initiation of volitional utterances via a dedicated network of vocal selective neurons that might have been exploited during the evolution of Broca's area.

Neuronal representations of reward-predicting cues and outcome history with movement in the frontal cortex

Transformation of sensory inputs to goal-directed actions requires estimation of sensory-cue values based on outcome history. We conduct wide-field and two-photon calcium imaging of the mouse neocortex during classical conditioning with two cues with different water-reward probabilities. Although licking movement dominates the area-averaged activity over the whole dorsal neocortex, the dorsomedial frontal cortex (dmFrC) affects other dorsal frontal cortical activities, and its inhibition extinguishes differences in anticipatory licking between the cues. Many dorsal frontal and medial prefrontal cortical neurons are task related. Subsets of these neurons are more excited by the low-reward-predicting cue or unrewarded outcomes than by the high-reward-predicting cue or rewarded outcomes, respectively. Task-related activities of these neurons and the others are counterbalanced, so that population activity appears dominated by licking. The reward-predicting cue and outcome history are most strongly represented in dmFrC. Our results suggest that dmFrC is crucial for initiating cortical processes to select or inhibit action.