Activation of pyramidal neurons in the infralimbic cortex alleviates LPS-induced depressive-like behavior in mice.

The infralimbic (IL) cortex dysfunction has been implicated in major depressive disorder (MDD), yet the precise cellular and molecular mechanisms remain poorly understood. In this study, we investigated the role of layer V pyramidal neurons in a mouse model of MDD induced by repeated lipopolysaccharide (LPS) administration. Our results demonstrate that three days of systemic LPS administration induced depressive-like behavior and upregulated mRNA levels of interleukin-1ß (IL-1ß), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-ß (TGF-ß) in the IL cortex. Electrophysiological recordings revealed a significant decrease in the intrinsic excitability of layer V pyramidal neurons in the IL following systemic LPS exposure. Importantly, chemogenetic activation of IL pyramidal neurons ameliorated LPS-induced depressive-like behavior. Additionally, LPS administration significantly increased microglial activity in the IL, as evidenced by a greater number of Ionized calcium binding adaptor molecule-1 (IBA-1)-positive cells. Morphometric analysis further unveiled enlarged soma, decreased branch numbers, and shorter branch lengths of microglial cells in the IL cortex following LPS exposure. Moreover, the activation of pyramidal neurons by clozapine-N-oxide increased the microglia branch length but did not change branch number or cytosolic area. These results collectively suggest that targeted activation of pyramidal neurons in the IL cortex mitigates microglial response and ameliorates depressive-like behaviors induced by systemic LPS administration. Therefore, our findings offer potential therapeutic targets for the development of interventions aimed at alleviating depressive symptoms by modulating IL cortical circuitry and microglial activity.

Mouse hippocampal CA1 VIP interneurons detect novelty in the environment and support recognition memory.

In the CA1 hippocampus, vasoactive intestinal polypeptide-expressing interneurons (VIP-INs) play a prominent role in disinhibitory circuit motifs. However, the specific behavioral conditions that lead to circuit disinhibition remain uncertain. To investigate the behavioral relevance of VIP-IN activity, we employed wireless technologies allowing us to monitor and manipulate their function in freely behaving mice. Our findings reveal that, during spatial exploration in new environments, VIP-INs in the CA1 hippocampal region become highly active, facilitating the rapid encoding of novel spatial information. Remarkably, both VIP-INs and pyramidal neurons (PNs) exhibit increased activity when encountering novel changes in the environment, including context- and object-related alterations. Concurrently, somatostatin- and parvalbumin-expressing inhibitory populations show an inverse relationship with VIP-IN and PN activity, revealing circuit disinhibition that occurs on a timescale of seconds. Thus, VIP-IN-mediated disinhibition may constitute a crucial element in the rapid encoding of novelty and the acquisition of recognition memory.

Female-specific dysfunction of sensory neocortical circuits in a mouse model of autism mediated by mGluR5 and estrogen receptor α.

Little is known of the brain mechanisms that mediate sex-specific autism symptoms. Here, we demonstrate that deletion of the autism spectrum disorder (ASD)-risk gene, Pten, in neocortical pyramidal neurons (NSEPten knockout [KO]) results in robust cortical circuit hyperexcitability selectively in female mice observed as prolonged spontaneous persistent activity states. Circuit hyperexcitability in females is mediated by metabotropic glutamate receptor 5 (mGluR5) and estrogen receptor α (ERα) signaling to mitogen-activated protein kinases (Erk1/2) and de novo protein synthesis. Pten KO layer 5 neurons have a female-specific increase in mGluR5 and mGluR5-dependent protein synthesis. Furthermore, mGluR5-ERα complexes are generally elevated in female cortices, and genetic reduction of ERα rescues enhanced circuit excitability, protein synthesis, and neuron size selectively in NSEPten KO females. Female NSEPten KO mice display deficits in sensory processing and social behaviors as well as mGluR5-dependent seizures. These results reveal mechanisms by which sex and a high-confidence ASD-risk gene interact to affect brain function and behavior.

Plasma membrane calcium ATPase powered by glycolysis is the main mechanism for calcium clearance in the hippocampal pyramidal neuron.

AIMS: This study sought to elucidate the primary ATP-dependent mechanisms involved in clearing cytosolic Ca2+ in neurons and determine the predominant ATP-generating pathway-glycolysis or tricarboxylic acid cycle/oxidative phosphorylation (TCA/OxPhos)-associated with these mechanisms in hippocampal pyramidal neurons. MAIN METHODS: Our investigation involved evaluating basal Ca2+ levels and analyzing the kinetic characteristics of evoked neuronal Ca2+ transients after selectively combined the inhibition/blockade of key ATP-dependent mechanisms with the suppression of either TCA/OxPhos or glycolytic ATP sources. KEY FINDINGS: Our findings unveiled that the plasma membrane Ca2+ ATPase (PMCA) serves as the principal ATP-dependent mechanism for clearance cytosolic Ca2+ in hippocampal pyramidal neurons, both during rest and neuronal activity. Remarkably, during cellular activity, PMCA relies on ATP derived from glycolysis, challenging the traditional notion of neuronal reliance on TCA/OxPhos for ATP. Other mechanisms for Ca2+ clearance in pyramidal neurons, such as SERCA and NCX, appear to be dependent on TCA/OxPhos. Interestingly, at rest, the ATP required to fuel PMCA and SERCA, the two main mechanisms to keep resting Ca2+, seems to originate from a source other than glycolysis or the TCA/OxPhos. SIGNIFICANCE: These findings underscore the vital role of glycolysis in bolstering PMCA neuronal function to uphold Ca2+ homeostasis. Moreover, they elucidate the varying dependencies of cytoplasmic Ca2+ clearance mechanisms on distinct energy sources for their operation.

Repeated Activation of Pyramidal Neurons in the Prefrontal Cortex Alters Microglial Phenotype in Male Mice.

Aberrant neuronal activity in the cortex alters microglia phenotype and function in several contexts, including chronic psychologic stress and neurodegenerative disease. Recent findings even suggest that heightened levels of neuronal activity spur microglia to phagocytose synapses, with potential impacts on cognition and behavior. Thus, the present studies were designed to determine if activation of neurons alone-independent of disease or dysfunction-is sufficient to alter microglial phenotype in the medial prefrontal cortex (mPFC), a brain region critical in emotion regulation and cognition. In these studies, we used both an adeno-associated virus-mediated and Cre-dependent chemogenetic [designer receptors exclusively activated by designer drugs (DREADD)] approach to repeatedly activate excitatory pyramidal neurons (CaMKIIa+) neurons in the mPFC. Various molecular, cytometric, and behavioral endpoints were examined. Recurrent DREADD-induced neuronal activation led to pronounced changes in microglial density, clustering, and morphology in the mPFC and increased microglia-specific transcripts implicated in synaptic pruning (e.g., Csf1r, Cd11b). Further analyses revealed that the magnitude of DREADD-induced neuronal activation was significantly correlated with measures of microglial morphology in the mPFC. These alterations in microglial phenotype coincided with an increase in microglial lysosome volume in the mPFC and selective deficits in working memory function. Altogether, these findings indicate that repeated neuronal activation alone is sufficient to drive changes in microglia phenotype and function in the mPFC. Future studies using optogenetic and chemogenetic approaches to manipulate neural circuits need to consider microglial and other nonneuronal contributions to physiologic and behavioral outcomes. SIGNIFICANCE STATEMENT: Microglia are highly attuned to fluctuations in neuronal activity. Here we show that repeated activation of pyramidal neurons in the prefrontal cortex induces broad changes in microglia phenotype; this includes upregulation of pathways associated with microglial proliferation, microglia-neuron interactions, and lysosome induction. Our findings suggest that studies using chemogenetic or optogenetic approaches to manipulate neural circuits should be mindful of indirect effects on nonneuronal cells and their potential contribution to measured outcomes.

Top-down input modulates visual context processing through an interneuron-specific circuit.

Visual stimuli that deviate from the current context elicit augmented responses in the primary visual cortex (V1). These heightened responses, known as "deviance detection," require local inhibition in the V1 and top-down input from the anterior cingulate area (ACa). Here, we investigated the mechanisms by which the ACa and V1 interact to support deviance detection. Local field potential recordings in mice during an oddball paradigm showed that ACa-V1 synchrony peaks in the theta/alpha band (≈10 Hz). Two-photon imaging in the V1 revealed that mainly pyramidal neurons exhibited deviance detection, while contextually redundant stimuli increased vasoactive intestinal peptide (VIP)-positive interneuron (VIP) activity and decreased somatostatin-positive interneuron (SST) activity. Optogenetic drive of ACa-V1 inputs at 10 Hz activated V1-VIPs but inhibited V1-SSTs, mirroring the dynamics present during the oddball paradigm. Chemogenetic inhibition of V1-VIPs disrupted Aca-V1 synchrony and deviance detection in the V1. These results outline temporal and interneuron-specific mechanisms of top-down modulation that support visual context processing.

Id2 GABAergic interneurons comprise a neglected fourth major group of cortical inhibitory cells.

Cortical GABAergic interneurons (INs) represent a diverse population of mainly locally projecting cells that provide specialized forms of inhibition to pyramidal neurons and other INs. Most recent work on INs has focused on subtypes distinguished by expression of Parvalbumin (PV), Somatostatin (SST), or Vasoactive Intestinal Peptide (VIP). However, a fourth group that includes neurogliaform cells (NGFCs) has been less well characterized due to a lack of genetic tools. Here, we show that these INs can be accessed experimentally using intersectional genetics with the gene Id2. We find that outside of layer 1 (L1), the majority of Id2 INs are NGFCs that express high levels of neuropeptide Y (NPY) and exhibit a late-spiking firing pattern, with extensive local connectivity. While much sparser, non-NGFC Id2 INs had more variable properties, with most cells corresponding to a diverse group of INs that strongly expresses the neuropeptide CCK. In vivo, using silicon probe recordings, we observed several distinguishing aspects of NGFC activity, including a strong rebound in activity immediately following the cortical down state during NREM sleep. Our study provides insights into IN diversity and NGFC distribution and properties, and outlines an intersectional genetics approach for further study of this underappreciated group of INs.

Developmental loss of ErbB4 in PV interneurons disrupts state-dependent cortical circuit dynamics.

GABAergic inhibition plays an important role in the establishment and maintenance of cortical circuits during development. Neuregulin 1 (Nrg1) and its interneuron-specific receptor ErbB4 are key elements of a signaling pathway critical for the maturation and proper synaptic connectivity of interneurons. Using conditional deletions of the ERBB4 gene in mice, we tested the role of this signaling pathway at two developmental timepoints in parvalbumin-expressing (PV) interneurons, the largest subpopulation of cortical GABAergic cells. Loss of ErbB4 in PV interneurons during embryonic, but not late postnatal development leads to alterations in the activity of excitatory and inhibitory cortical neurons, along with severe disruption of cortical temporal organization. These impairments emerge by the end of the second postnatal week, prior to the complete maturation of the PV interneurons themselves. Early loss of ErbB4 in PV interneurons also results in profound dysregulation of excitatory pyramidal neuron dendritic architecture and a redistribution of spine density at the apical dendritic tuft. In association with these deficits, excitatory cortical neurons exhibit normal tuning for sensory inputs, but a loss of state-dependent modulation of the gain of sensory responses. Together these data support a key role for early developmental Nrg1/ErbB4 signaling in PV interneurons as a powerful mechanism underlying the maturation of both the inhibitory and excitatory components of cortical circuits.

Thyroid Hormone Transporters MCT8 and OATP1C1 Are Expressed in Pyramidal Neurons and Interneurons in the Adult Motor Cortex of Human and Macaque Brain.

Monocarboxylate transporter 8 (MCT8) and organic anion transporter polypeptide 1C1 (OATP1C1) are thyroid hormone (TH) transmembrane transporters that play an important role in the availability of TH for neural cells, allowing their proper development and function. It is important to define which cortical cellular subpopulations express those transporters to explain why MCT8 and OATP1C1 deficiency in humans leads to dramatic alterations in the motor system. By means of immunohistochemistry and double/multiple labeling immunofluorescence in adult human and monkey motor cortices, we demonstrate the presence of both transporters in long-projection pyramidal neurons and in several types of short-projection GABAergic interneurons in both species, suggesting a critical position of these transporters for modulating the efferent motor system. MCT8 is present at the neurovascular unit, but OATP1C1 is only present in some of the large vessels. Both transporters are expressed in astrocytes. OATP1C1 was unexpectedly found, only in the human motor cortex, inside the Corpora amylacea complexes, aggregates linked to substance evacuation towards the subpial system. On the basis of our findings, we propose an etiopathogenic model that emphasizes these transporters' role in controlling excitatory/inhibitory motor cortex circuits in order to understand some of the severe motor disturbances observed in TH transporter deficiency syndromes.

Chemogenetic rectification of the inhibitory tone onto hippocampal neurons reverts autistic-like traits and normalizes local expression of estrogen receptors in the Ambra1+/- mouse model of female autism.

Female, but not male, mice with haploinsufficiency for the proautophagic Ambra1 gene show an autistic-like phenotype associated with hippocampal circuits dysfunctions which include loss of parvalbuminergic interneurons (PV-IN), decrease in the inhibition/excitation ratio, and abundance of immature dendritic spines on CA1 pyramidal neurons. Given the paucity of data relating to female autism, we exploit the Ambra1+/- female model to investigate whether rectifying the inhibitory input onto hippocampal principal neurons (PN) rescues their ASD-like phenotype at both the systems and circuits level. Moreover, being the autistic phenotype exclusively observed in the female mice, we control the effect of the mutation and treatment on hippocampal expression of estrogen receptors (ER). Here we show that excitatory DREADDs injected in PV_Cre Ambra1+/- females augment the inhibitory input onto CA1 principal neurons (PN), rescue their social and attentional impairments, and normalize dendritic spine abnormalities and ER expression in the hippocampus. By providing the first evidence that hippocampal excitability jointly controls autistic-like traits and ER in a model of female autism, our findings identify an autophagy deficiency-related mechanism of hippocampal neural and hormonal dysregulation which opens novel perspectives for treatments specifically designed for autistic females.

Expression of the P53 Protein and Morphological Changes in Neurons in the Pyramidal Layer of the Hippocampus After Simulation of Surgical Interventions in the Nasal Cavity in Rats.

BACKGROUND/AIMS: To determine the role of surgical stress on the formation of p53-positive and dark neurons (DN) in the hippocampus, and to examine the parallelism of their formation in the pyramidal layer of the hippocampus. METHODS: Simulated septoplasty was performed on 20 Wistar rats. The hippocampus and dentate gyrus (DG) were examined, in which the number of DN and p53-positive neurons was determined at 2, 4 and 6 days after surgery. In each rat, 10 brain slices were stained with antibodies to p53 protein with Meyer's haematoxylin and 10 slices were stained with Nissl toluidine blue. Hippocampal subfields CA1, CA2, CA3 and DG were studied. In the pyramidal subfield layer, the absolute number of neurons that were nuclear antibody-positive to p53 protein was counted, as well as the number of dark neurons. The counting area in each subfield was 20934±1260 µm2. Neurons are counted using the Aperio ImageScope program. For the histological specimen analysis, the ImageJ software was used. The data obtained using cell counting methods were presented as mean ± SE. Then, they were compared between both groups using a t-test SPSS 21software. RESULTS: Compared with the control group (n = 5), the number of DN and p53-positive neurons increased in experimental animals at all periods. A direct relationship was obtained between the increase in the number of DN and p53-positive neurons in the hippocampal formation. Septoplasty simulation in rats results in the pathogenetic cascades onset, which, in its turn, changes the morpho-functional properties of neurons of the pyramidal layer of the hippocampus and contributes to their neuroplasticity. Activation of NMDS receptors of neurons during stress apparently, initiates two ways of neuron life - the beginning of p53 protein expression and the DN formation. Both ways can finally lead to apoptosis. CONCLUSION: The formation of dark neurons and the expression of the p53 protein in them are most likely to be interconnected and can probably provide neuroprotective mechanisms.

Direction selectivity of inhibitory interneurons in mouse barrel cortex differs between interneuron subtypes.

GABAergic interneurons represent ∼15% to 20% of all cortical neurons, but their diversity grants them unique roles in cortical circuits. In the barrel cortex, responses of excitatory neurons to stimulation of facial whiskers are direction selective, whereby excitation is maximized over a narrow range of angular deflections. Whether GABAergic interneurons are also direction selective is unclear. Here, we use two-photon-guided whole-cell recordings in the barrel cortex of anesthetized mice and control whisker stimulation to measure direction selectivity in defined interneuron subtypes. Selectivity is ubiquitous in interneurons, but tuning sharpness varies across populations. Vasoactive intestinal polypeptide (VIP) interneurons are as selective as pyramidal neurons, but parvalbumin (PV) interneurons are more broadly tuned. Furthermore, a majority (2/3) of somatostatin (SST) interneurons receive direction-selective inhibition, with the rest receiving direction-selective excitation. Sensory evoked activity in the barrel cortex is thus cell-type specific, suggesting that interneuron subtypes make distinct contributions to cortical representations of stimuli.

GHSR1a deficiency suppresses inhibitory drive on dCA1 pyramidal neurons and contributes to memory reinforcement.

Growth hormone secretagogue receptor 1a (GHSR1a)-the receptor for orexigenic hormone ghrelin-is a G protein-coupled receptor that is widely distributed in the brain, including the hippocampus. Studies have demonstrated that genetic deletion of GHSR1a affects memory, suggesting the importance of ghrelin/GHSR1a signaling in cognitive control. However, current reports are controversial, and the mechanism underlying GHSR1a modulation of memory is uncertain. Here, we first report that global GHSR1a knockout enhances hippocampus-dependent memory, facilitates initial LTP in dorsal hippocampal Schaffer Collateral-CA1 synapses, and downregulates Akt activity in the hippocampus. Moreover, we show that the intrinsic excitability of GAD67+ interneurons-rather than neighboring pyramidal neurons in the dCA1-is suppressed by GHSR1a deletion, an effect that is antagonized by acute application of the Akt activator SC79. In addition, the inhibitory postsynaptic currents (IPSCs) on dCA1 pyramidal neurons are selectively reduced in mice with a GHSR1a deficiency. Finally, we demonstrate that selectively increasing the excitability of parvalbumin-expressing interneurons by hM3Dq-DREADDs increases IPSCs on dCA1 pyramidal neurons and normalizes memory in Ghsr1a KO mice. Our findings thus reveal a novel mechanism underlying memory enhancement of GHSR1a deficiency and herein support an adverse effect of GHSR1a signaling in hippocampus-dependent memory processes.

GDNF Increases Inhibitory Synaptic Drive on Principal Neurons in the Hippocampus via Activation of the Ret Pathway.

Glial cell line-derived neurotrophic factor (GDNF) has been shown to counteract seizures when overexpressed or delivered into the brain in various animal models of epileptogenesis or chronic epilepsy. The mechanisms underlying this effect have not been investigated. We here demonstrate for the first time that GDNF enhances GABAergic inhibitory drive onto mouse pyramidal neurons by modulating postsynaptic GABAA receptors, particularly in perisomatic inhibitory synapses, by GFRα1 mediated activation of the Ret receptor pathway. Other GDNF receptors, such as NCAM or Syndecan3, are not contributing to this effect. We observed similar alterations by GDNF in human hippocampal slices resected from epilepsy patients. These data indicate that GDNF may exert its seizure-suppressant action by enhancing GABAergic inhibitory transmission in the hippocampal network, thus counteracting the increased excitability of the epileptic brain. This new knowledge can contribute to the development of novel, more precise treatment strategies based on a GDNF gene therapy approach.

Rate and oscillatory switching dynamics of a multilayer visual microcircuit model.

The neocortex is organized around layered microcircuits consisting of a variety of excitatory and inhibitory neuronal types which perform rate- and oscillation-based computations. Using modeling, we show that both superficial and deep layers of the primary mouse visual cortex implement two ultrasensitive and bistable switches built on mutual inhibitory connectivity motives between somatostatin, parvalbumin, and vasoactive intestinal polypeptide cells. The switches toggle pyramidal neurons between high and low firing rate states that are synchronized across layers through translaminar connectivity. Moreover, inhibited and disinhibited states are characterized by low- and high-frequency oscillations, respectively, with layer-specific differences in frequency and power which show asymmetric changes during state transitions. These findings are consistent with a number of experimental observations and embed firing rate together with oscillatory changes within a switch interpretation of the microcircuit.

Novel mechanism of hypoxic neuronal injury mediated by non-excitatory amino acids and astroglial swelling.

In ischemic stroke and post-traumatic brain injury (TBI), blood-brain barrier disruption leads to leaking plasma amino acids (AA) into cerebral parenchyma. Bleeding in hemorrhagic stroke and TBI also release plasma AA. Although excitotoxic AA were extensively studied, little is known about non-excitatory AA during hypoxic injury. Hypoxia-induced synaptic depression in hippocampal slices becomes irreversible with non-excitatory AA, alongside their intracellular accumulation and increased tissue electrical resistance. Four non-excitatory AA (l-alanine, glycine, l-glutamine, l-serine: AGQS) at plasmatic concentrations were applied to slices from mice expressing EGFP in pyramidal neurons or astrocytes during normoxia or hypoxia. Two-photon imaging, light transmittance (LT) changes, and electrophysiological field recordings followed by electron microscopy in hippocampal CA1 st. radiatum were used to monitor synaptic function concurrently with cellular swelling and injury. During normoxia, AGQS-induced increase in LT was due to astroglial but not neuronal swelling. LT raise during hypoxia and AGQS manifested astroglial and neuronal swelling accompanied by a permanent loss of synaptic transmission and irreversible dendritic beading, signifying acute damage. Neuronal injury was not triggered by spreading depolarization which did not occur in our experiments. Hypoxia without AGQS did not cause cell swelling, leaving dendrites intact. Inhibition of NMDA receptors prevented neuronal damage and irreversible loss of synaptic function. Deleterious effects of AGQS during hypoxia were prevented by alanine-serine-cysteine transporters (ASCT2) and volume-regulated anion channels (VRAC) blockers. Our findings suggest that astroglial swelling induced by accumulation of non-excitatory AA and release of excitotoxins through antiporters and VRAC may exacerbate the hypoxia-induced neuronal injury.

The Relationship between p53-Positive Neurons and Dark Neurons in the Hippocampus of Rats after Surgical Interventions on the Nasal Septum.

The study evaluates the dependence of p53 protein expression on the appearance of dark neurons (DNs) in the hippocampus in rats during experimental modeling of septoplasty. Septoplasty simulation was carried out on 15 sexually mature male Wistar rats. We studied histological sections of the hippocampus stained with Nissl toluidine blue and antibodies to the p53 protein. In the CA1 subfield, the number of p53-positive neurons significantly increased on the 2nd, 4th (p < 0.001) and 6th days (p < 0.05). In the dynamics, the peak of the growth of p53 protein expression in the cytoplasm of CA1 and CA2 neurons fell on the 2-4th day after the operation, and on the 6th day the number of these neurons decreased (p < 0.001). In the cytoplasm of CA3 neurons in all periods after surgery, an increase in the expression of the p53 protein as compared to the control group was noted. In the CA1 pyramidal layer, the number of DNs decreased on the 6th day (p < 0.001). In CA2, after 2 days, a minimum of DNs as compared with the 4th day (p < 0.001) was noted. In CA3, on the 4th day, there was a peak in DNs as compared with the rest of the days (p < 0.001). A positive strong association was found in all periods of assessment and in all subfields of the hippocampus between an increase in the number of dark and p53-positive neurons. The appearance of dark and p53-positive neurons in the hippocampal formation in rats after simulating septoplasty are typical responses of nervous tissue to stress. It is obvious that the expression of the p53 protein is associated with the basophilia of the cytoplasm of neurons, their morpho-functional state. Presumably, the p53 protein can trigger not only the activation of damaged neurons in the hippocampus but also play a neuroprotective role. Upcoming studies should determine the role of the p53 protein in the further fate of damaged neurons in the pyramidal layer and differentiate the mechanisms of its expression.

Highly unstable heterogeneous representations in VIP interneurons of the anterior cingulate cortex.

A hallmark of the anterior cingulate cortex (ACC) is its functional heterogeneity. Functional and imaging studies revealed its importance in the encoding of anxiety-related and social stimuli, but it is unknown how microcircuits within the ACC encode these distinct stimuli. One type of inhibitory interneuron, which is positive for vasoactive intestinal peptide (VIP), is known to modulate the activity of pyramidal cells in local microcircuits, but it is unknown whether VIP cells in the ACC (VIPACC) are engaged by particular contexts or stimuli. Additionally, recent studies demonstrated that neuronal representations in other cortical areas can change over time at the level of the individual neuron. However, it is not known whether stimulus representations in the ACC remain stable over time. Using in vivo Ca2+ imaging and miniscopes in freely behaving mice to monitor neuronal activity with cellular resolution, we identified individual VIPACC that preferentially activated to distinct stimuli across diverse tasks. Importantly, although the population-level activity of the VIPACC remained stable across trials, the stimulus-selectivity of individual interneurons changed rapidly. These findings demonstrate marked functional heterogeneity and instability within interneuron populations in the ACC. This work contributes to our understanding of how the cortex encodes information across diverse contexts and provides insight into the complexity of neural processes involved in anxiety and social behavior.

Inhibition of the Akt/PKB Kinase Increases Nav1.6-Mediated Currents and Neuronal Excitability in CA1 Hippocampal Pyramidal Neurons.

In neurons, changes in Akt activity have been detected in response to the stimulation of transmembrane receptors. However, the mechanisms that lead to changes in neuronal function upon Akt inhibition are still poorly understood. In the present study, we interrogate how Akt inhibition could affect the activity of the neuronal Nav channels with while impacting intrinsic excitability. To that end, we employed voltage-clamp electrophysiological recordings in heterologous cells expressing the Nav1.6 channel isoform and in hippocampal CA1 pyramidal neurons in the presence of triciribine, an inhibitor of Akt. We showed that in both systems, Akt inhibition resulted in a potentiation of peak transient Na+ current (INa) density. Akt inhibition correspondingly led to an increase in the action potential firing of the CA1 pyramidal neurons that was accompanied by a decrease in the action potential current threshold. Complementary confocal analysis in the CA1 pyramidal neurons showed that the inhibition of Akt is associated with the lengthening of Nav1.6 fluorescent intensity along the axonal initial segment (AIS), providing a mechanism for augmented neuronal excitability. Taken together, these findings provide evidence that Akt-mediated signal transduction might affect neuronal excitability in a Nav1.6-dependent manner.

The Roles of IL-22 and Its Receptor in the Regulation of Inflammatory Responses in the Brain.

Interleukin (IL)-22 is a potent mediator of inflammatory responses. The IL-22 receptor consists of the IL-22Rα and IL-10Rß subunits. Previous studies have shown that IL-22Rα expression is restricted to non-hematopoietic cells in the skin, pancreas, intestine, liver, lung, and kidney. Although IL-22 is involved in the development of inflammatory responses, there have been no reports of its role in brain inflammation. Here, we used RT-PCR, Western blotting, flow cytometry, immunohistochemical, and microarray analyses to examine the role of IL-22 and expression of IL-22Rα in the brain, using the microglial cell line, hippocampal neuronal cell line, and inflamed mouse brain tissue. Treatment of BV2 and HT22 cells with recombinant IL-22 increased the expression levels of the pro-inflammatory cytokines IL-6 and TNF-α, as well as cyclooxygenase (COX)-2 and prostaglandin E2. We also found that the JNK and STAT3 signaling pathways play an important role in IL-22-mediated increases in inflammatory mediators. Microarray analyses revealed upregulated expression of inflammation-related genes in IL-22-treated HT22 cells. Finally, we found that IL-22Rα is spontaneously expressed in the brain and is upregulated in inflamed mouse brain. Overall, our results demonstrate that interaction of IL-22 with IL-22Rα plays a role in the development of inflammatory responses in the brain.