Cortical Circuits Research Articles

The homeostatic effects of the RE-1 silencing transcription factor on cortical networks are altered under ictogenic conditions in the mouse.

The Repressor Element-1 Silencing Transcription Factor (REST) is an epigenetic master regulator playing a crucial role in the nervous system. In early developmental stages, REST downregulation promotes neuronal differentiation and the acquisition of the neuronal phenotype. In addition, postnatal fluctuations in REST expression contribute to shaping neuronal networks and maintaining network homeostasis. Here we investigate the role of the early postnatal deletion of neuronal REST in the assembly and strength of excitatory and inhibitory synaptic connections. We investigated excitatory and inhibitory synaptic transmission by patch-clamp recordings in acute neocortical slices in a conditional knockout mouse model (RestGTi) in which Rest was deleted by delivering PHP.eB adeno-associated viruses encoding CRE recombinase under the control of the human synapsin I promoter in the lateral ventricles of P0-P1 pups. We show that, under physiological conditions, Rest deletion increased the intrinsic excitability of principal cortical neurons in the primary visual cortex and the density and strength of excitatory synaptic connections impinging on them, without affecting inhibitory transmission. Conversely, in the presence of a pathological excitation/inhibition imbalance induced by pentylenetetrazol, Rest deletion prevented the increase in synaptic excitation and decreased seizure severity. The data indicate that REST exerts distinct effects on the excitability of cortical circuits depending on whether it acts under physiological conditions or in the presence of pathologic network hyperexcitability. In the former case, REST preserves a correct excitatory/inhibitory balance in cortical circuits, while in the latter REST loses its homeostatic activity and may become pro-epileptogenic.

Prefrontal cortical dynorphin peptidergic transmission constrains threat-driven behavioral and network states

Prefrontal cortical (PFC) circuits provide top-down control of threat reactivity. This includes ventromedial PFC (vmPFC) circuitry, which plays a role in suppressing fear-related behavioral states. Dynorphin (Dyn) has been implicated in mediating negative affect and maladaptive behaviors induced by severe threats and is expressed in limbic circuits, including the vmPFC. However, there is a critical knowledge gap in our understanding of how vmPFC Dyn-expressing neurons and Dyn transmission detect threats and regulate expression of defensive behaviors. Here, we demonstrate that Dyn cells are broadly activated by threats and release Dyn locally in the vmPFC to limit passive defensive behaviors. We further demonstrate that vmPFC Dyn-mediated signaling promotes a switch of vmPFC networks to a fear-related state. In conclusion, we reveal a previously unknown role of vmPFC Dyn neurons and Dyn neuropeptidergic transmission in suppressing defensive behaviors in response to threats via state-driven changes in vmPFC networks.

Modulation of Corticospinal Excitability during Action Observation in Patients with Disorders of Consciousness.

Brain imaging studies have recently provided some evidence in favor of covert cognitive processes that are ongoing in patients with disorders of consciousness (DoC) (e.g., a minimally conscious state and vegetative state/unresponsive wakefulness syndrome) when engaged in passive sensory stimulation or active tasks such as motor imagery. In this exploratory study, we used transcranial magnetic stimulation (TMS) of the motor cortex to assess modulations of corticospinal excitability induced by action observation in eleven patients with DoC. Action observation is known to facilitate corticospinal excitability in healthy subjects, unveiling how the observer's motor system maps others' actions onto her/his motor repertoire. Additional stimuli were non-biological motion and acoustic startle stimuli, considering that sudden and loud acoustic stimulation is known to lower corticospinal excitability in healthy subjects. The results indicate that some form of motor resonance is spared in a subset of patients with DoC, with some significant difference between biological and non-biological motion stimuli. However, there was no covariation between corticospinal excitability and the type of DoC diagnosis (i.e., whether diagnosed with VS/UWS or MCS). Similarly, no covariation was detected with clinical changes between admission and discharge in clinical outcome measures. Both motor resonance and the difference between the resonance with biological/non-biological motion discrimination correlated with the amplitude of the N20 somatosensory evoked potentials, following the stimulation of the median nerve at the wrist (i.e., the temporal marker signaling the activation of the contralateral primary somatosensory cortex). Moreover, the startle-evoking stimulus produced an anomalous increase in corticospinal excitability, suggesting a functional dissociation between cortical and subcortical circuits in patients with DoC. Further work is needed to better comprehend the conditions in which corticospinal facilitation occurs and whether and how they may relate to individual clinical parameters.

A primary sensory cortical interareal feedforward inhibitory circuit for tacto-visual integration

Tactile sensation and vision are often both utilized for the exploration of objects that are within reach though it is not known whether or how these two distinct sensory systems combine such information. Here in mice, we used a combination of stereo photogrammetry for 3D reconstruction of the whisker array, brain-wide anatomical tracing and functional connectivity analysis to explore the possibility of tacto-visual convergence in sensory space and within the circuitry of the primary visual cortex (VISp). Strikingly, we find that stimulation of the contralateral whisker array suppresses visually evoked activity in a tacto-visual sub-region of VISp whose visual space representation closely overlaps with the whisker search space. This suppression is mediated by local fast-spiking interneurons that receive a direct cortico-cortical input predominantly from layer 6 neurons located in the posterior primary somatosensory barrel cortex (SSp-bfd). These data demonstrate functional convergence within and between two primary sensory cortical areas for multisensory object detection and recognition.

Somatostatin interneurons control the timing of developmental desynchronization in cortical networks

Synchronous neuronal activity is a hallmark of the developing brain. In the mouse cerebral cortex, activity decorrelates during the second week of postnatal development, progressively acquiring the characteristic sparse pattern underlying the integration of sensory information. The maturation of inhibition seems critical for this process, but the interneurons involved in this crucial transition of network activity in the developing cortex remain unknown. Using invivo longitudinal two-photon calcium imaging during the period that precedes the change from highly synchronous to decorrelated activity, we identify somatostatin-expressing (SST+) interneurons as critical modulators of this switch in mice. Modulation of the activity of SST+ cells accelerates or delays the decorrelation of cortical network activity, a process that involves regulating the maturation of parvalbumin-expressing (PV+) interneurons. SST+ cells critically link sensory inputs with local circuits, controlling the neural dynamics in the developing cortex while modulating the integration of other interneurons into nascent cortical circuits.

Top–down modulation in canonical cortical circuits with short-term plasticity

Cortical dynamics and computations are strongly influenced by diverse GABAergic interneurons, including those expressing parvalbumin (PV), somatostatin (SST), and vasoactive intestinal peptide (VIP). Together with excitatory (E) neurons, they form a canonical microcircuit and exhibit counterintuitive nonlinear phenomena. One instance of such phenomena is response reversal, whereby SST neurons show opposite responses to top-down modulation via VIP depending on the presence of bottom-up sensory input, indicating that the network may function in different regimes under different stimulation conditions. Combining analytical and computational approaches, we demonstrate that model networks with multiple interneuron subtypes and experimentally identified short-term plasticity mechanisms can implement response reversal. Surprisingly, despite not directly affecting SST and VIP activity, PV-to-E short-term depression has a decisive impact on SST response reversal. We show how response reversal relates to inhibition stabilization and the paradoxical effect in the presence of several short-term plasticity mechanisms demonstrating that response reversal coincides with a change in the indispensability of SST for network stabilization. In summary, our work suggests a role of short-term plasticity mechanisms in generating nonlinear phenomena in networks with multiple interneuron subtypes and makes several experimentally testable predictions.

Antipsychotic drugs selectively decorrelate long-range interactions in deep cortical layers.

Psychosis is characterized by a diminished ability of the brain to distinguish externally driven activity patterns from self-generated activity patterns. Antipsychotic drugs are a class of small molecules with relatively broad binding affinity for a variety of neuromodulator receptors that, in humans, can prevent or ameliorate psychosis. How these drugs influence the function of cortical circuits, and in particular their ability to distinguish between externally and self-generated activity patterns, is still largely unclear. To have experimental control over self-generated sensory feedback, we used a virtual reality environment in which the coupling between movement and visual feedback can be altered. We then used widefield calcium imaging to determine the cell type-specific functional effects of antipsychotic drugs in mouse dorsal cortex under different conditions of visuomotor coupling. By comparing cell type-specific activation patterns between locomotion onsets that were experimentally coupled to self-generated visual feedback and locomotion onsets that were not coupled, we show that deep cortical layers were differentially activated in these two conditions. We then show that the antipsychotic drug clozapine disrupted visuomotor integration at locomotion onsets also primarily in deep cortical layers. Given that one of the key components of visuomotor integration in cortex is long-range cortico-cortical connections, we tested whether the effect of clozapine was detectable in the correlation structure of activity patterns across dorsal cortex. We found that clozapine as well as two other antipsychotic drugs, aripiprazole and haloperidol, resulted in a strong reduction in correlations of layer 5 activity between cortical areas and impaired the spread of visuomotor prediction errors generated in visual cortex. Our results are consistent with the interpretation that a major functional effect of antipsychotic drugs is a selective alteration of long-range layer 5-mediated communication.

Antipsychotic drugs selectively decorrelate long-range interactions in deep cortical layers

Psychosis is characterized by a diminished ability of the brain to distinguish externally driven activity patterns from self-generated activity patterns. Antipsychotic drugs are a class of small molecules with relatively broad binding affinity for a variety of neuromodulator receptors that, in humans, can prevent or ameliorate psychosis. How these drugs influence the function of cortical circuits, and in particular their ability to distinguish between externally and self-generated activity patterns, is still largely unclear. To have experimental control over self-generated sensory feedback, we used a virtual reality environment in which the coupling between movement and visual feedback can be altered. We then used widefield calcium imaging to determine the cell type-specific functional effects of antipsychotic drugs in mouse dorsal cortex under different conditions of visuomotor coupling. By comparing cell type-specific activation patterns between locomotion onsets that were experimentally coupled to self-generated visual feedback and locomotion onsets that were not coupled, we show that deep cortical layers were differentially activated in these two conditions. We then show that the antipsychotic drug clozapine disrupted visuomotor integration at locomotion onsets also primarily in deep cortical layers. Given that one of the key components of visuomotor integration in cortex is long-range cortico-cortical connections, we tested whether the effect of clozapine was detectable in the correlation structure of activity patterns across dorsal cortex. We found that clozapine as well as two other antipsychotic drugs, aripiprazole and haloperidol, resulted in a strong reduction in correlations of layer 5 activity between cortical areas and impaired the spread of visuomotor prediction errors generated in visual cortex. Our results are consistent with the interpretation that a major functional effect of antipsychotic drugs is a selective alteration of long-range layer 5-mediated communication.

Reservoir computing system based on mutually delay-coupled semiconductor lasers with optical feedback

Reservoir Computing (RC), an evolution from Recurrent Neural Networks (RNN), not only represents a unique machine learning paradigm, but also serves as a neuromorphic framework that mirrors the intricate cortical circuits of the human brain. This paper proposes another new photonic RC system based on four basic photonic reservoir computing architectures (single photonic RC system, the parallel photonic RC system, the dual-feedback loop-based photonic RC system and the mutually coupled photonic RC system). System proposed uses optical injection for signal input and retains two parallel responsive semiconductor lasers (R-SLs) with self-feedback loops. Meanwhile, two relatively independent R-SLs are mutually coupled via two coupling lines. The new photonic RC system adds only two sections of fiber compared to the parallel photonic RC system and the mutually coupled photonic RC system. The experiments show that the system proposed has significant advantages on the nonlinear auto regressive moving average series tasks, the chaotic time series prediction tasks and the waveform classification task. More importantly, the memory capacity of system proposed can be adjust by controlling the delay time of the self-feedback loops, so it has higher memory capacity to handle the higher order nonlinear auto regressive moving average tasks (NARMA20 and NARMA30) after optimizing the parameters.

Distinct and Convergent Alterations of Entorhinal Cortical Circuits in Two Mouse Models for Alzheimer's Disease and Related Disorders.

The impairment of neural circuits controlling cognitive processes has been implicated in the pathophysiology of Alzheimer's disease and related disorders (ADRD). However, it is largely unclear what circuits are specifically changed in ADRD, particularly at the early stage. Our goal of this study is to reveal the functional changes in the circuit of entorhinal cortex (EC), an interface between neocortex and hippocampus, in AD. Electrophysiological, optogenetic and chemogenetic approaches were used to examine and manipulate entorhinal cortical circuits in amyloid-β familial AD model (5×FAD) and tauopathy model (P301S Tau). We found that, compared to wild-type mice, electrical stimulation of EC induced markedly smaller responses in subiculum (hippocampal output) of 5×FAD mice (6-month-old), suggesting that synaptic communication in the EC to subiculum circuit is specifically blocked in this AD model. In addition, optogenetic stimulation of glutamatergic terminals from prefrontal cortex (PFC) induced smaller responses in EC of 5×FAD and P301S Tau mice (6-month-old), suggesting that synaptic communication in the PFC to EC pathway is compromised in both ADRD models. Chemogenetic activation of PFC to EC pathway did not affect the bursting activity of EC neurons in 5×FAD mice, but partially restored the diminished EC neuronal activity in P301S Tau mice. These data suggest that 5×FAD mice has a specific impairment of short-range hippocampal gateway (EC to subiculum), which may be caused by amyloid-β deposits; while two ADRD models have a common impairment of long-range cortical to hippocampal circuit (PFC to EC), which may be caused by microtubule/tau-based transport deficits. These circuit deficits provide a pathophysiological basis for unique and common impairments of various cognitive processes in ADRD conditions.

Altered Cortical Gyrification Morphology in Nonsucidal Self-injury

IntroductionNonsuicidal self-injury (NSSI) is defined as deliberate and direct damage to one’s body tissues without any suicidal intent. NSSI is now recognized as a major risk factor for suicide and is prevalent among adolescents, with prevalence rates ranging from 7.5% to 46.5%, leading to increased interest in the pathophysiology of NSSI. This study aimed to examine cortical gyrification morphology, a neurobiological index of cortical folding and patterning, among unmedicated individuals with NSSI, which is prevalent in adolescents and young adults.Objectives The main objective of this study is to compare cortical morphological abnormalities between individuals with NSSI and controls in terms of the local gyrification index (LGI), the ratio of the smooth cortical surface area at each vertex to the corresponding sulcal folds. In addition, we hypothesized that the LGI, a stable neurodevelopmental marker of cortical and subcortical circuit intergrity, would correlate with clinical measures in youth with NSSI.Methods A total of 101 individuals with NSSI and 100 age-, gender-, and handedness-matched controls completed self-report questionnaires and structural magnetic resonance imaging (MRI) data were acquired on a 3T Siemens scanner. A surface-based analysis was conducted using the Computational Anatomy Toolbox (CAT12) in Statistical Parametric Mapping (SPM12). Partial correlation analysis was also performed using R software to investigate the association between the LGI values extracted from the region of interest (ROI) and clinical symptoms, including depression, anxiety, emotion dysregulation, and anhedonia in individuals with NSSI.ResultsIndividuals with NSSI showed significantly increased LGI in the right insula sulcus and left superior temporal sulcus (STS), along with decreased LGI in the right calcarine and left superior parietal sulcus (SPS), compared to controls (5000 permutation correction, threshold-free cluster enhancement with a threshold of p < .05). In addition, higher LGI in left STS was correlated with greater scores of the Beck Anxiety Inventory (r = 0.22, p < .05) and of the Impulse Control Difficulties subscale of the Difficulties in Emotion Regulation Scale (r = 0.34, p < .001). Conversely, reduced LGI of the right calcarine was associated with a higher score on the Anhedonia subscale of the Beck Depression Inventory (r = -0.23, p < .05) within individuals with NSSI.ConclusionsThis study identified hypergyria in the right insular and left STS and hypogyria in the right calcarine and left SPS in individuals with NSSI. The former pattern was associated with anxiety and impulse control difficulties, and the latter was with anhedonia. This study is the first to alter distinct neurodevelopmental patterns of local gyrification and their correlations with clinical manifestations in individuals with NSSI.Disclosure of InterestNone Declared

Intensity- and frequency-specific effects of transcranial alternating current stimulation are explained by network dynamics

Objective. Transcranial alternating current stimulation (tACS) can be used to non-invasively entrain neural activity and thereby cause changes in local neural oscillatory power. Despite its increased use in cognitive and clinical neuroscience, the fundamental mechanisms of tACS are still not fully understood. Approach. We developed a computational neuronal network model of two-compartment pyramidal neurons (PY) and inhibitory interneurons, which mimic the local cortical circuits. We modeled tACS with electric field strengths that are achievable in human applications. We then simulated intrinsic network activity and measured neural entrainment to investigate how tACS modulates ongoing endogenous oscillations. Main results. The intensity-specific effects of tACS are non-linear. At low intensities (<0.3 mV mm−1), tACS desynchronizes neural firing relative to the endogenous oscillations. At higher intensities (>0.3 mV mm−1), neurons are entrained to the exogenous electric field. We then further explore the stimulation parameter space and find that the entrainment of ongoing cortical oscillations also depends on stimulation frequency by following an Arnold tongue. Moreover, neuronal networks can amplify the tACS-induced entrainment via synaptic coupling and network effects. Our model shows that PY are directly entrained by the exogenous electric field and drive the inhibitory neurons. Significance. The results presented in this study provide a mechanistic framework for understanding the intensity- and frequency-specific effects of oscillating electric fields on neuronal networks. This is crucial for rational parameter selection for tACS in cognitive studies and clinical applications.

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.

Dopamine D2 Receptor Modulates Exercise Related Effect on Cortical Excitation/Inhibition and Motor Skill Acquisition.

Exercise is known to benefit motor skill learning in health and neurological disease. Evidence from brain stimulation, genotyping, and Parkinson's disease studies converge to suggest that the dopamine D2 receptor, and shifts in the cortical excitation and inhibition (E:I) balance, are prime candidates for the drivers of exercise-enhanced motor learning. However, causal evidence using experimental pharmacological challenge is lacking. We hypothesized that the modulatory effect of the dopamine D2 receptor on exercise-induced changes in the E:I balance would determine the magnitude of motor skill acquisition. To test this, we measured exercise-induced changes in excitation and inhibition using paired-pulse transcranial magnetic stimulation (TMS) in 22 healthy female and male humans, and then had participants learn a novel motor skill-the sequential visual isometric pinch task (SVIPT). We examined the effect of D2 receptor blockade (800 mg sulpiride) on these measures within a randomized, double-blind, placebo-controlled design. Our key result was that motor skill acquisition was driven by an interaction between the D2 receptor and E:I balance. Specifically, poorer skill learning was related to an attenuated shift in the E:I balance in the sulpiride condition, whereas this interaction was not evident in placebo. Our results demonstrate that exercise-primed motor skill acquisition is causally influenced by D2 receptor activity on motor cortical circuits.

The Spiraling Cognitive-Emotional Brain: Combinatorial, Reciprocal, and Reentrant Macro-organization.

This article proposes a framework for understanding the macro-scale organization of anatomical pathways in the mammalian brain. The architecture supports flexible behavioral decisions across a spectrum of spatio-temporal scales. The proposal emphasizes the combinatorial, reciprocal, and reentrant connectivity-called CRR neuroarchitecture-between cortical, BG, thalamic, amygdala, hypothalamic, and brainstem circuits. Thalamic nuclei, especially midline/intralaminar nuclei, are proposed to act as hubs routing the flow of signals between noncortical areas and pFC. The hypothalamus also participates in multiregion circuits via its connections with cortex and thalamus. At slower timescales, long-range behaviors integrate signals across levels of the neuroaxis. At fast timescales, parallel engagement of pathways allows urgent behaviors while retaining flexibility. Overall, the proposed architecture enables context-dependent, adaptive behaviors spanning proximate to distant spatio-temporal scales. The framework promotes an integrative perspective and a distributed, heterarchical view of brain function.

Lateral Connections Improve Generalizability of Learning in a Simple Neural Network.

To navigate the world around us, neural circuits rapidly adapt to their environment learning generalizable strategies to decode information. When modeling these learning strategies, network models find the optimal solution to satisfy one task condition but fail when introduced to a novel task or even a different stimulus in the same space. In the experiments described in this letter, I investigate the role of lateral gap junctions in learning generalizable strategies to process information. Lateral gap junctions are formed by connexin proteins creating an open pore that allows for direct electrical signaling between two neurons. During neural development, the rate of gap junctions is high, and daughter cells that share similar tuning properties are more likely to be connected by these junctions. Gap junctions are highly plastic and get heavily pruned throughout development. I hypothesize that they mediate generalized learning by imprinting the weighting structure within a layer to avoid overfitting to one task condition. To test this hypothesis, I implemented a feedforward probabilistic neural network mimicking a cortical fast spiking neuron circuit that is heavily involved in movement. Many of these cells are tuned to speeds that I used as the input stimulus for the network to estimate. When training this network using a delta learning rule, both a laterally connected network and an unconnected network can estimate a single speed. However, when asking the network to estimate two or more speeds, alternated in training, an unconnected network either cannot learn speed or optimizes to a singular speed, while the laterally connected network learns the generalizable strategy and can estimate both speeds. These results suggest that lateral gap junctions between neurons enable generalized learning, which may help explain learning differences across life span.

An insular cortical circuit required for itch sensation and aversion

Itch encompasses both sensory and emotional dimensions, with the two dimensions reciprocally exacerbating each other. However, whether a shared neural circuit mechanism governs both dimensions remains elusive. Here, we report that the anterior insular cortex (AIC) is activated by both histamine-dependent and -independent itch stimuli. The activation of AIC elicits aversive emotion and exacerbates pruritogen-induced itch sensation and aversion. Mechanistically, AIC excitatory neurons project to the GABAergic neurons in the dorsal bed nucleus of the stria terminalis (dBNST). Manipulating the activity of the AIC → dBNST pathway affects both itch sensation and itch-induced aversion. Our study discovers the shared neural circuit (AIC→ dBNST pathway) underlying the itch sensation and aversion, highlights the critical role of the AIC as a central hub for the itch processing, and provides a framework to understand the neural mechanisms underlying the sensation and emotion interaction.

Synaptic and dendritic architecture of different types of hippocampal somatostatin interneurons.

GABAergic inhibitory neurons fundamentally shape the activity and plasticity of cortical circuits. A major subset of these neurons contains somatostatin (SOM); these cells play crucial roles in neuroplasticity, learning, and memory in many brain areas including the hippocampus, and are implicated in several neuropsychiatric diseases and neurodegenerative disorders. Two main types of SOM-containing cells in area CA1 of the hippocampus are oriens-lacunosum-moleculare (OLM) cells and hippocampo-septal (HS) cells. These cell types show many similarities in their soma-dendritic architecture, but they have different axonal targets, display different activity patterns in vivo, and are thought to have distinct network functions. However, a complete understanding of the functional roles of these interneurons requires a precise description of their intrinsic computational properties and their synaptic interactions. In the current study we generated, analyzed, and make available several key data sets that enable a quantitative comparison of various anatomical and physiological properties of OLM and HS cells in mouse. The data set includes detailed scanning electron microscopy (SEM)-based 3D reconstructions of OLM and HS cells along with their excitatory and inhibitory synaptic inputs. Combining this core data set with other anatomical data, patch-clamp electrophysiology, and compartmental modeling, we examined the precise morphological structure, inputs, outputs, and basic physiological properties of these cells. Our results highlight key differences between OLM and HS cells, particularly regarding the density and distribution of their synaptic inputs and mitochondria. For example, we estimated that an OLM cell receives about 8,400, whereas an HS cell about 15,600 synaptic inputs, about 16% of which are GABAergic. Our data and models provide insight into the possible basis of the different functionality of OLM and HS cell types and supply essential information for more detailed functional models of these neurons and the hippocampal network.

PAK3 activation promotes the tangential to radial migration switch of cortical interneurons by increasing leading process dynamics and disrupting cell polarity

Mutations of PAK3, a p21-activated kinase, are associated in humans with cognitive deficits suggestive of defective cortical circuits and with frequent brain structural abnormalities. Most human variants no longer exhibit kinase activity. Since GABAergic interneurons express PAK3 as they migrate within the cortex, we here examined the role of PAK3 kinase activity in the regulation of cortical interneuron migration. During the embryonic development, cortical interneurons migrate a long distance tangentially and then re-orient radially to settle in the cortical plate, where they contribute to cortical circuits. We showed that interneurons expressing a constitutively kinase active PAK3 variant (PAK3-ca) extended shorter leading processes and exhibited unstable polarity. In the upper cortical layers, they entered the cortical plate and extended radially oriented processes. In the deep cortical layers, they exhibited erratic non-processive migration movements and accumulated in the deep pathway. Pharmacological inhibition of PAK3 kinase inhibited the radial migration switch of interneurons to the cortical plate and reduced their accumulation in the deep cortical layers. Interneurons expressing a kinase dead PAK3 variant (PAK3-kd) developed branched leading processes, maintained the same polarity during migration and exhibited processive and tangentially oriented movements in the cortex. These results reveal that PAK3 kinase activity, by promoting leading process shortening and cell polarity changes, inhibits the tangential processive migration of interneurons and favors their radial re- orientation and targeting to the cortical plate. They suggest that patients expressing PAK3 variants with impaired kinase activity likely present alterations in the cortical targeting of their GABAergic interneurons.

Behavioral strategy shapes activation of the Vip-Sst disinhibitory circuit in visual cortex

In complex environments, animals can adopt diverse strategies to find rewards. How distinct strategies differentially engage brain circuits is not well understood. Here, we investigate this question, focusing on the cortical Vip-Sst disinhibitory circuit between vasoactive intestinal peptide-postive (Vip) interneurons and somatostatin-positive (Sst) interneurons. We characterize the behavioral strategies used by mice during a visual change detection task. Using a dynamic logistic regression model, we find that individual mice use mixtures of a visual comparison strategy and a statistical timing strategy. Separately, mice also have periods of task engagement and disengagement. Two-photon calcium imaging shows large strategy-dependent differences in neural activity in excitatory, Sst inhibitory, and Vip inhibitory cells in response to both image changes and image omissions. In contrast, task engagement has limited effects on neural population activity. We find that the diversity of neural correlates of strategy can be understood parsimoniously as the increased activation of the Vip-Sst disinhibitory circuit during the visual comparison strategy, which facilitates task-appropriate responses.