Cortical Circuits Research Articles

Sex-specific age-related changes in excitatory and inhibitory intra-cortical circuits in mouse primary auditory cortex.

A common impairment in aging is age-related hearing loss (presbycusis), which manifests as impaired spectrotemporal processing. Presbycusis can be caused by a dysfunction of the peripheral and central auditory system and these dysfunctions might differ between the sexes. To date, the circuit mechanisms in the central nervous system responsible for age-related auditory dysfunction remain mostly unknown. In the auditory cortex (ACtx), aging is accompanied by alteration in normal inhibitory (GABA) neurotransmission and changes in excitatory (NMDA and AMPA) synapses, but which circuits are affected has been unclear. Here we investigated how auditory cortical microcircuits change with age and if sex-dependent differences existed. We performed laser-scanning photostimulation (LSPS) combined with whole-cell patch clamp recordings from Layer (L) 2/3 cells in primary auditory cortex (A1) in young adult (2-3 months) and aged (older than 18 months) male and female CBA/CaJ mice which have normal peripheral hearing. We found that L2/3 cells in aged male animals display functional hypoconnectivity of inhibitory circuits originating from L2/3 and L4. Compared to cells from young adult mice, cells from aged male mice have weaker excitatory connections from L2/3. We also observed an increased diversity of excitatory and inhibitory inputs. These results suggest a sex-specific reduction and diversification in excitatory and inhibitory intralaminar cortical circuits in aged mice compared with young adult animals. We speculate that these unbalanced changes in cortical circuits contribute to the functional manifestations of age-related hearing loss in both males and females.Significance Statement A common impairment in aging is age-related hearing loss (presbycusis) which can be caused by a dysfunction of the peripheral and central auditory system. Impaired spectrotemporal processing in the auditory cortex is thought to underlie some of these impairments. We compare auditory cortex circuits in vitro in young adult (∼P60) and aged (∼P585) CBA mice. We find a sex-specific reduction in excitatory and inhibitory intralaminar cortical circuits in aged mice compared with young adult animals. We speculate that these unbalanced changes in cortical circuits underlie the differential functional manifestations of age-related hearing loss in both males and females.

From experimental phenomena to computational models: Exploring the synchronization mechanisms of phase-locked stimulation in the hippocampal–thalamic–cortical circuit for memory consolidation

Closed-loop phase-locking stimulation has been experimentally demonstrated to facilitate memory consolidation, which is believed to rely on the coordinated interactions among slow waves in multi-regional cortex, thalamocortical sleep spindles, and hippocampal ripples. However, the mechanisms through which this stimulation influences memory consolidation have not been thoroughly investigated. Therefore, starting from experimental phenomena, we computationally explored the synchronization mechanisms of memory consolidation in the hippocampal–thalamocortical (HTC) loop based on a firing rate model, and further reproduced the established effects of stimulation therapy on memory consolidation. The results indicate that excitatory connections between the cortex and hippocampus play a crucial role in the memory consolidation process. Additionally, our improved inhibitory closed-loop phase-locking stimulation protocol exhibits a more enhanced effect on memory consolidation compared to previous experimental stimulation schemes. Moreover, non-invasive stimulation shows lower side effects, costs, and implementation difficulties compared to invasive stimulation. Consequently, we further designed and explored the modulatory effects of a non-invasive magnetic–acoustic stimulation protocol. The results suggest that this non-invasive magnetic–acoustic stimulation yields effects comparable to those of existing invasive experimental deep brain stimulation. Our findings may provide new evidence and perspectives for understanding the neural mechanisms of memory processes and offer potential theoretical foundations for innovative non-invasive therapeutic strategies.

NREM sleep improves behavioral performance by desynchronizing cortical circuits.

Sleep improves cognitive performance, yet little is known about the neural mechanisms of this improvement. We performed multielectrode recording in macaque visual and dorsolateral prefrontal cortex while animals performed a visual discrimination task before and after non-rapid eye movement (NREM) sleep. Although sleep induces synchronized fluctuations in population activity across cortical areas, the post-sleep population activity became more desynchronized relative to the pre-sleep state. The changes after sleep were correlated with an increase in information encoded in population activity in each area and improved behavioral performance. Electrically stimulating visual cortex at 4 hertz emulated the beneficial effects of sleep on network and perceptual performance. A large-scale neural network model indicated that asymmetric depression of local intracortical synapses is consistent with the observed changes in neural activity after sleep.

Neurofeedback-induced desynchronization of sensorimotor rhythm elicits pre-movement downregulation of intracortical inhibition that shortens simple reaction time in humans: a double-blind sham-controlled randomized study

Abstract Sensorimotor rhythm event-related desynchronization (SMR-ERD) is associated with the activities of cortical inhibitory circuits in the motor cortex. The self-regulation of SMR-ERD through neurofeedback training has demonstrated that successful SMR-ERD regulation improves motor performance. However, the training-induced changes in neural dynamics in the motor cortex underlying performance improvement remain unclear. Here, we hypothesized that SMR-neurofeedback based on motor imagery reduces cortical inhibitory activities during motor preparation, leading to shortened reaction time due to the repetitive recruitment of neural populations shared with motor imagery and movement preparation. To test this, we conducted a double-blind, sham-controlled study on twenty-four participants using neurofeedback training and pre- and post-training evaluation for simple reaction time tests and cortical inhibitory activity using short-interval intracortical inhibition (SICI). The results showed that veritable neurofeedback training effectively enhanced SMR-ERD in healthy male and female participants, accompanied by reduced simple reaction times and pre-movement SICI. Furthermore, SMR-ERD changes correlated with changes in pre-movement cortical disinhibition, and the disinhibition magnitude correlated with behavioral changes. These results suggest that SMR-neurofeedback modulates cortical inhibitory circuits during movement preparation, thereby enhancing motor performance.

The gamma rhythm as a guardian of brain health.

Gamma oscillations in brain activity (30-150 Hz) have been studied for over 80 years. Although in the past three decades significant progress has been made to try to understand their functional role, a definitive answer regarding their causal implication in perception, cognition, and behavior still lies ahead of us. Here, we first review the basic neural mechanisms that give rise to gamma oscillations and then focus on two main pillars of exploration. The first pillar examines the major theories regarding their functional role in information processing in the brain, also highlighting critical viewpoints. The second pillar reviews a novel research direction that proposes a therapeutic role for gamma oscillations, namely the gamma entrainment using sensory stimulation (GENUS). We extensively discuss both the positive findings and the issues regarding reproducibility of GENUS. Going beyond the functional and therapeutic role of gamma, we propose a third pillar of exploration, where gamma, generated endogenously by cortical circuits, is essential for maintenance of healthy circuit function. We propose that four classes of interneurons, namely those expressing parvalbumin (PV), vasointestinal peptide (VIP), somatostatin (SST), and nitric oxide synthase (NOS) take advantage of endogenous gamma to perform active vasomotor control that maintains homeostasis in the neuronal tissue. According to this hypothesis, which we call GAMER (GAmma MEdiated ciRcuit maintenance), gamma oscillations act as a 'servicing' rhythm that enables efficient translation of neural activity into vascular responses that are essential for optimal neurometabolic processes. GAMER is an extension of GENUS, where endogenous rather than entrained gamma plays a fundamental role. Finally, we propose several critical experiments to test the GAMER hypothesis.

Transplanted deep-layer cortical neuroblasts integrate into host neural circuits and alleviate motor defects in hypoxic-ischemic encephalopathy injured mice

BackgroundHypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal disability and mortality. Although intensive studies and therapeutic approaches, there are limited restorative treatments till now. Human embryonic stem cell (hESCs)-derived cortical neural progenitors have shown great potentials in ischemic stroke in adult brain. However, it is unclear whether they are feasible for cortical reconstruction in immature brain with hypoxic-ischemic encephalopathy.MethodsBy using embryonic body (EB) neural differentiation method combined with DAPT pre-treatment and quantitative cell transplantation, human cortical neuroblasts were obtained and transplanted into the cortex of hypoxic-ischemic injured brain with different dosages 2 weeks after surgery. Then, immunostaining, whole-cell patch clamp recordings and behavioral testing were applied to explore the graft survival and proliferation, fate commitment of cortical neuroblasts in vitro, neural circuit reconstruction and the therapeutic effects of cortical neuroblasts in HIE brain.ResultsTransplantation of human cortical neural progenitor cells (hCNPs) in HIE-injured cortex exhibited long-term graft overgrowth. DAPT pre-treatment successfully synchronized hCNPs from different developmental stages (day 17, day 21, day 28) to deep layer cortical neuroblasts which survived well in HIE injured brain and greatly prevented graft overgrowth after transplantation. Importantly, the cortical neuroblasts primarily differentiated into deep-layer cortical neurons and extended long axons to their projection targets, such as the cortex, striatum, thalamus, and internal capsule in both ipsilateral and contralateral HIE-injured brain. The transplanted cortical neurons established synapses with host cortical neurons and exhibited spontaneous excitatory or inhibitory post-synaptic currents (sEPSCs or sIPSCs) five months post-transplantation. Rotarod and open field tests showed greatly improved animal behavior by intra-cortex transplantation of deep layer cortical neuroblasts in HIE injured brain.ConclusionsTransplanted hESCs derived cortical neuroblasts survive, project to endogenous targets, and integrate into host cortical neural circuits to rescue animal behavior in the HIE-injured brain without graft overgrowth, providing a novel and safe cell replacement strategy for the future treatment of HIE.

Clinical efficacy of low-dose Perampanel correlates with neurophysiological changes in familial adult myoclonus epilepsy 2.

Familial adult myoclonus epilepsy (FAME) management relies on antiseizure medications (ASMs), which inadequately address myoclonus and cortical tremor. This study evaluates Perampanel (PER), an AMPA-receptor antagonist, for treating FAME symptoms. Fifteen FAME2 patients participated in an observational prospective study. They received up to 6 mg daily of PER and underwent Unified-Myoclonus-Rating-Scale (UMRS) before and after treatment. Neurophysiological evaluations, including somatosensory evoked potentials (SEPs) and transcranial magnetic stimulation (TMS), assessed PER's impact on cortical glutamatergic excitatory and GABAergic inhibitory circuits. PER treatment significantly reduced UMRS total scores (p = 0.001) and action-myoclonus subscores (p = 0.002), irrespective of disease duration, age at onset, or testing time (p >0.05). Patients with more severe baseline myoclonus demonstrated significant improvements. Neurophysiological assessments revealed a PER-induced decrease in sensorimotor hyperexcitability, characterized by diminished N33 amplitudes, attenuated glutamatergic facilitation, and enhanced GABAergic inhibition in the motor cortex. In conclusion, low-dose PER is well tolerated and effective in alleviating myoclonus in FAME2 patients, supported by its modulatory effects on glutamatergic and GABAergic neuronal circuits. Plain Language Summary: This study investigated the effects of low-dose perampanel in individuals with Familial Adult Myoclonus Epilepsy2 (FAME2), a hereditary condition characterized by epilepsy and tremors. Perampanel, an antiepileptic drug, blocks AMPA receptors in the brain, reducing excessive neural activity that causes seizures and abnormal movements. The results showed significant symptom improvement, which correlated with changes in brain activity as measured by neurophysiological tests. This study suggests that perampanel helps regulate abnormal brain signals and may help managing FAME2 symptoms.

Entropy of Neuronal Spike Patterns.

Neuronal spike patterns are the fundamental units of neural communication in the brain, which is still not fully understood. Entropy measures offer a quantitative framework to assess the variability and information content of these spike patterns. By quantifying the uncertainty and informational content of neuronal patterns, entropy measures provide insights into neural coding strategies, synaptic plasticity, network dynamics, and cognitive processes. Here, we review basic entropy metrics and then we provide examples of recent advancements in using entropy as a tool to improve our understanding of neuronal processing. It focuses especially on studies on critical dynamics in neural networks and the relation of entropy to predictive coding and cortical communication. We highlight the necessity of expanding entropy measures from single neurons to encompass multi-neuronal activity patterns, as cortical circuits communicate through coordinated spatiotemporal activity patterns, called neuronal packets. We discuss how the sequential and partially stereotypical nature of neuronal packets influences the entropy of cortical communication. Stereotypy reduces entropy by enhancing reliability and predictability in neural signaling, while variability within packets increases entropy, allowing for greater information capacity. This balance between stereotypy and variability supports both robustness and flexibility in cortical information processing. We also review challenges in applying entropy to analyze such spatiotemporal neuronal spike patterns, notably, the "curse of dimensionality" in estimating entropy for high-dimensional neuronal data. Finally, we discuss strategies to overcome these challenges, including dimensionality reduction techniques, advanced entropy estimators, sparse coding schemes, and the integration of machine learning approaches. Thus, this work summarizes the most recent developments on how entropy measures contribute to our understanding of principles underlying neural coding.

Distinct inhibitory neurons differently shape neuronal codes for sound intensity in the auditory cortex.

Cortical circuits contain multiple types of inhibitory neurons which shape how information is processed within neuronal networks. Here, we asked whether somatostatin-expressing (SST) and vasoactive intestinal peptide-expressing (VIP) inhibitory neurons have distinct effects on population neuronal responses to noise bursts of varying intensities. We optogenetically stimulated SST or VIP neurons while simultaneously measuring the calcium responses of populations of hundreds of neurons in the auditory cortex of male and female awake, head-fixed mice to sounds. Upon SST neuronal activation, noise bursts representations became more discrete for different intensity levels, relying on cell identity rather than strength. By contrast, upon VIP neuronal activation, noise bursts of different intensity level activated overlapping neuronal populations, albeit at different response strengths. At the single-cell level, SST and VIP neuronal activation differentially modulated the response-level curves of monotonic and nonmonotonic neurons. SST neuronal activation effects were consistent with a shift of the neuronal population responses toward a more localist code with different cells responding to sounds of different intensity. By contrast, VIP neuronal activation shifted responses towards a more distributed code, in which sounds of different intensity level are encoded in the relative response of similar populations of cells. These results delineate how distinct inhibitory neurons in the auditory cortex dynamically control cortical population codes. Different inhibitory neuronal populations may be recruited under different behavioral demands, depending on whether categorical or invariant representations are advantageous for the task.Significance Statement Information about sounds is represented in the auditory cortex by neuronal population activity that has a characteristic sparse structure. Cortical neuronal populations comprise multiple types of excitatory and inhibitory neurons. Here, we find that activating different types of inhibitory neurons differentially controls population neuronal representations, with one type of inhibitory neurons increasing the differences in the identity of the cells recruited to represent the different sounds, and another inhibitory neuron type changing the relative activity level of overlapping neuronal populations. Such transformations may be beneficial for different types of auditory behaviors, suggesting that these different types of inhibitory neurons may be recruited under different behavioral constraints in optimizing neuronal representations of sounds.

Primate thalamic nuclei select abstract rules and shape prefrontal dynamics.

Flexible behavior depends on abstract rules to generalize beyond specific instances, and outcome monitoring to adjust actions. Cortical circuits are posited to read out rules from high-dimensional representations of task-relevant variables in prefrontal cortex (PFC). We instead hypothesized that converging inputs from PFC, directly or via basal ganglia (BG), enable thalamus to select rules. We measured activity across PFC and connected thalamic nuclei of monkeys applying rules. Abstract rule information first appeared in ventroanterior thalamus (VA) - the main thalamic hub between BG and PFC. Mediodorsal thalamus (MD) also represented rule information before PFC, persisting to help maintain activation of relevant PFC cell ensembles. MD, a major recipient of midbrain dopamine input, was first to represent information about behavioral outcomes. A PFC-BG-thalamus model reproduced key findings, and thalamic-lesion modeling disrupted PFC rule representations. This suggests that thalamus selects high-level cognitive information from PFC and monitors behavioral outcomes of these selections.

Within-individual organization of the human cognitive cerebellum: Evidence for closely juxtaposed, functionally specialized regions.

Specific regions in the cognitive cerebellum are connected to distinct cerebral association networks. Do these cerebellar regions exhibit functional specialization similar to the cerebral cortex? Here, we mapped the cerebellum within intensively studied participants (N = 15) first using connectivity to estimate regions linked to specific networks and then prospectively testing functional response properties in task data within each individual's own idiosyncratic anatomy. A large megacluster extending across Crus I/II was consistently found with subregions linked to five higher-order association networks. A more variable smaller association cluster was found in lobule IX. Within the Crus I/II megacluster, specific cerebellar regions responded to domain-flexible cognitive control, while juxtaposed regions differentially responded to language, social, and spatial/episodic task demands. Similarly organized clusters also exist in the caudate consistent with the presence of multiple basal ganglia-cerebellar-cerebral cortical circuits that maintain functional specialization across their entire distributed extents.

Common and contrasting effects of 5-HTergic signaling in pyramidal cells and SOM interneurons of the mouse cortex.

Serotonin (5-hydroxytryptamine, 5-HT) is a powerful modulator of neuronal activity within the central nervous system and dysfunctions of the serotonergic system have been linked to several neuropsychiatric disorders such as major depressive disorders or schizophrenia. The anterior cingulate cortex (aCC) plays an important role in cognitive capture of stimuli and valence processing and it is densely innervated by serotonergic fibers from the nucleus raphe. In order to understand how pathophysiological 5-HT signalling can lead to neuropsychiatric diseases, it is important to understand the physiological actions of 5-HT on cortical circuits. Therefore, we combined electrophysiological recordings with pharmacology and immunocytochemistry to investigate the effects of 5-HT on Somatostatin-positive interneurons (SOM-INs) and compared these to supragranular pyramidal cells (PCs). This comparison allowed us to identify common and contrasting effects of 5-HT on SOM-INs and PCs of the aCC resulting in a specific modulation of the excitation-to-inhibition balance in PCs but not in SOM-INs.

Repetitive sensory stimulation potentiates and recruits sensory-evoked cortical population activity.

Sensory experience and learning are thought to be associated with plasticity of neocortical circuits. Repetitive sensory stimulation can induce long-term potentiation (LTP) of cortical excitatory synapses in anesthetized mice; however, it is unclear if these phenomena are associated with sustained changes in activity during wakefulness. Here we used time-lapse, calcium imaging of layer (L) 2/3 neurons in the primary somatosensory cortex (S1), in awake male mice, to assess the effects of a bout of rhythmic whisker stimulation (RWS) at a frequency by which rodents sample objects. We found that RWS induced a 1h-increase in whisker-evoked L2/3 neuronal activity in most cells. This was not observed for whiskers functionally connected to distant cortical columns. We also found that RWS could heterogeneously recruit or suppress whisker-evoked activity in different populations of neurons. Vasoactive intestinal-peptide-expressing (VIP) interneurons, which promote plasticity through disinhibition of pyramidal neurons, were found to exclusively elevate activity during RWS. These findings indicate that cortical neurons' representation of sensory input can be modulated over hours through repetitive sensory stimulation, which may be gated by activation of disinhibitory circuits.Significance statement Sensory experience and learning are thought to be associated with the plasticity of cortical synaptic circuits. Here, we tested how repeated sensory stimulation changes subsequent sensory-evoked responses, using the mouse somatosensory cortex as a model. This cortical area processes, among others, sensory information from the whiskers. We found that rhythmic whisker stimulation potentiated excitatory neuronal activity for an hour, and identified a disinhibitory interneuron-mediated mechanism that could gate this plasticity. This work increases our understanding of sensory learning and experience-dependent plasticity processes by demonstrating that cortical representations of sensory input are dynamic and are effectively modulated by repeated sensory stimulation.

Specific inhibition and disinhibition in the higher-order structure of a cortical connectome.

Neurons are thought to act as parts of assemblies with strong internal excitatory connectivity. Conversely, inhibition is often reduced to blanket inhibition with no targeting specificity. We analyzed the structure of excitation and inhibition in the MICrONS $mm^{3}$ dataset, an electron microscopic reconstruction of a piece of cortical tissue. We found that excitation was structured around a feed-forward flow in large non-random neuron motifs with a structure of information flow from a small number of sources to a larger number of potential targets. Inhibitory neurons connected with neurons in specific sequential positions of these motifs, implementing targeted and symmetrical competition between them. None of these trends are detectable in only pairwise connectivity, demonstrating that inhibition is structured by these large motifs. While descriptions of inhibition in cortical circuits range from non-specific blanket-inhibition to targeted, our results describe a form of targeting specificity existing in the higher-order structure of the connectome. These findings have important implications for the role of inhibition in learning and synaptic plasticity.

Synaptic interactions between stellate cells and parvalbumin interneurons in layer 2 of the medial entorhinal cortex are organized at the scale of grid cell clusters.

Interactions between excitatory and inhibitory neurons are critical to computations in cortical circuits but their organization is difficult to assess with standard electrophysiological approaches. Within the medial entorhinal cortex, representation of location by grid and other spatial cells involves circuits in layer 2 in which excitatory stellate cells interact with each other via inhibitory parvalbumin expressing interneurons. Whether this connectivity is structured to support local circuit computations is unclear. Here, we introduce strategies to address the functional organization of excitatory-inhibitory interactions using crossed Cre- and Flp-driver mouse lines to direct targeted presynaptic optogenetic activation and postsynaptic cell identification. We then use simultaneous patch-clamp recordings from postsynaptic neurons to assess their shared input from optically activated presynaptic populations. We find that extensive axonal projections support spatially organized connectivity between stellate cells and parvalbumin interneurons, such that direct connections are often, but not always, shared by nearby neurons, whereas multisynaptic interactions coordinate inputs to neurons with greater spatial separation. We suggest that direct excitatory-inhibitory synaptic interactions may operate at the scale of grid cell clusters, with local modules defined by excitatory-inhibitory connectivity, while indirect interactions may coordinate activity at the scale of grid cell modules.

A complex acoustical environment during development enhances auditory perception and coding efficiency in the zebra finch.

Sensory experience during development has lasting effects on perception and neural processing. Exposing juvenile animals to artificial stimuli influences the tuning and functional organization of the auditory cortex, but less is known about how the rich acoustical environments experienced by vocal communicators affect the processing of complex vocalizations. Here, we show that in zebra finches (Taeniopygia guttata), a colonial-breeding songbird species, exposure to a naturalistic social-acoustical environment during development has a profound impact on auditory perceptual behavior and on cortical-level auditory responses to conspecific song. Compared to birds raised by pairs in acoustic isolation, male and female birds raised in a breeding colony were better in an operant discrimination task at recognizing conspecific songs with and without masking colony noise. Neurons in colony-reared birds had higher average firing rates, selectivity, and discriminability, especially in the narrow-spiking, putatively inhibitory neurons of a higher-order auditory area, the caudomedial nidopallium (NCM). Neurons in colony-reared birds were also less correlated in their tuning and more efficient at encoding the spectrotemporal structure of conspecific song, and better at filtering out masking noise. These results suggest that the auditory cortex adapts to noisy, complex acoustical environments by strengthening inhibitory circuitry, functionally decoupling excitatory neurons while maintaining overall excitatory-inhibitory balance.

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.

Control of innate olfactory valence by segregated cortical amygdala circuits.

Animals exhibit innate behaviors that are stereotyped responses to specific evolutionarily relevant stimuli in the absence of prior learning or experience. These behaviors can be reduced to an axis of valence, whereby specific odors evoke approach or avoidance responses. The posterolateral cortical amygdala (plCoA) mediates innate attraction and aversion to odor. However, little is known about how this brain area gives rise to behaviors of opposing motivational valence. Here, we sought to define the circuit features of plCoA that give rise to innate attraction and aversion to odor. We characterized the physiology, gene expression, and projections of this structure, identifying a divergent, topographic organization that selectively controls innate attraction and avoidance to odor. First, we examined odor-evoked responses in these areas and found sparse encoding of odor identity, but not valence. We next considered a topographic organization and found that optogenetic stimulation of the anterior and posterior domains of plCoA elicits attraction and avoidance, respectively, suggesting a functional axis for valence. Using single cell and spatial RNA sequencing, we identified the molecular cell types in plCoA, revealing an anteroposterior gradient in cell types, whereby anterior glutamatergic neurons preferentially express VGluT2 and posterior neurons express VGluT1. Activation of these respective cell types recapitulates appetitive and aversive behaviors, and chemogenetic inhibition reveals partial necessity for responses to innate appetitive or aversive odors. Finally, we identified topographically organized circuits defined by projections, whereby anterior neurons preferentially project to medial amygdala, and posterior neurons preferentially project to nucleus accumbens, which are respectively sufficient and necessary for innate attraction and aversion. Together, these data advance our understanding of how the olfactory system generates stereotypic, hardwired attraction and avoidance, and supports a model whereby distinct, topographically distributed plCoA populations direct innate olfactory responses by signaling to divergent valence-specific targets, linking upstream olfactory identity to downstream valence behaviors, through a population code. This suggests a novel amygdala circuit motif in which valence encoding is represented not by the firing properties of individual neurons, but by population level identity encoding that is routed through divergent targets to mediate distinct behaviors of opposing appetitive and aversive responses.

Optogenetic Stimulation Recruits Cortical Neurons in a Morphology-Dependent Manner.

Single-photon optogenetics enables precise, cell-type-specific modulation of neuronal circuits, making it a crucial tool in neuroscience. Its miniaturization in the form of fully implantable wide-field stimulator arrays enables long-term interrogation of cortical circuits and bears promise for brain-machine interfaces for sensory and motor function restoration. However, achieving selective activation of functional cortical representations poses a challenge, as studies show that targeted optogenetic stimulation results in activity spread beyond one functional domain. While recurrent network mechanisms contribute to activity spread, here we demonstrate with detailed simulations of isolated pyramidal neurons from cats of unknown sex that already neuron morphology causes a complex spread of optogenetic activity at the scale of one cortical column. Since the shape of a neuron impacts its optogenetic response, we find that a single stimulator at the cortical surface recruits a complex spatial distribution of neurons that can be inhomogeneous and vary with stimulation intensity and neuronal morphology across layers. We explore strategies to enhance stimulation precision, finding that optimizing stimulator optics may offer more significant improvements than the preferentially somatic expression of the opsin through genetic targeting. Our results indicate that, with the right optical setup, single-photon optogenetics can precisely activate isolated neurons at the scale of functional cortical domains spanning several hundred micrometers.

Functional networks of inhibitory neurons orchestrate synchrony in the hippocampus.

Inhibitory interneurons are pivotal components of cortical circuits. Beyond providing inhibition, they have been proposed to coordinate the firing of excitatory neurons within cell assemblies. While the roles of specific interneuron subtypes have been extensively studied, their influence on pyramidal cell synchrony in vivo remains elusive. Employing an all-optical approach in mice, we simultaneously recorded hippocampal interneurons and pyramidal cells and probed the network influence of individual interneurons using optogenetics. We demonstrate that CA1 interneurons form a functionally interconnected network that promotes synchrony through disinhibition during awake immobility, while preserving endogenous cell assemblies. Our network model underscores the importance of both cell assemblies and dense, unspecific interneuron connectivity in explaining our experimental findings, suggesting that interneurons may operate not only via division of labor but also through concerted activity.