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The ability to suppress actions that lead to a negative outcome and explore alternative actions is necessary for optimal decision making. Although the basal ganglia have been implicated in these processes.sup.1-5, the circuit mechanisms underlying action selection and exploration remain unclear. Here, using a simple lateralized licking task, we show that indirect striatal projection neurons (iSPN) in the basal ganglia contribute to these processes through modulation of the superior colliculus (SC). Optogenetic activation of iSPNs suppresses contraversive licking and promotes ipsiversive licking. Activity in lateral superior colliculus (lSC), a region downstream of the basal ganglia, is necessary for task performance and predicts lick direction. Furthermore, iSPN activation suppresses ipsilateral lSC, but surprisingly excites contralateral lSC, explaining the emergence of ipsiversive licking. Optogenetic inactivation reveals inter-collicular competition whereby each hemisphere of the superior colliculus inhibits the other, thus allowing the indirect pathway to disinhibit the contralateral lSC and trigger licking. Finally, inactivating iSPNs impairs suppression of devalued but previously rewarded licking and reduces exploratory licking. Our results reveal that iSPNs engage the competitive interaction between lSC hemispheres to trigger a motor action and suggest a general circuit mechanism for exploration during action selection. Indirect striatal projection neurons in the basal ganglia modulate activity in the superior colliculus, thereby controlling selection and exploration of actions in response to a reward omission., Author(s): Jaeeon Lee [sup.1] , Bernardo L. Sabatini [sup.1] Author Affiliations: (1) Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, USA Main Activities of direct- and indirect-pathway [...]

Accurate navigation to a desired goal requires consecutive estimates of spatial relationships between the current position and future destination throughout the journey. Although neurons in the hippocampal formation can represent the position of an animal as well as its nearby trajectories.sup.1-7, their role in determining the destination of the animal has been questioned.sup.8,9. It is, thus, unclear whether the brain can possess a precise estimate of target location during active environmental exploration. Here we describe neurons in the rat orbitofrontal cortex (OFC) that form spatial representations persistently pointing to the subsequent goal destination of an animal throughout navigation. This destination coding emerges before the onset of navigation, without direct sensory access to a distal goal, and even predicts the incorrect destination of an animal at the beginning of an error trial. Goal representations in the OFC are maintained by destination-specific neural ensemble dynamics, and their brief perturbation at the onset of a journey led to a navigational error. These findings suggest that the OFC is part of the internal goal map of the brain, enabling animals to navigate precisely to a chosen destination that is beyond the range of sensory perception. Dedicated cells in the hippocampus and entorhinal cortex map an animal s instantaneous position in space; by contrast, its future goal location is represented in the orbitofrontal cortex, a structure within the broader circuit., Author(s): Raunak Basu [sup.1] , Robert Gebauer [sup.1] , Tim Herfurth [sup.1] , Simon Kolb [sup.1] , Zahra Golipour [sup.1] , Tatjana Tchumatchenko [sup.1] [sup.2] , Hiroshi T. Ito [sup.1] [...]

Microglia, the brain's resident macrophages, help to regulate brain function by removing dying neurons, pruning non-functional synapses, and producing ligands that support neuronal survival.sup.1. Here we show that microglia are also critical modulators of neuronal activity and associated behavioural responses in mice. Microglia respond to neuronal activation by suppressing neuronal activity, and ablation of microglia amplifies and synchronizes the activity of neurons, leading to seizures. Suppression of neuronal activation by microglia occurs in a highly region-specific fashion and depends on the ability of microglia to sense and catabolize extracellular ATP, which is released upon neuronal activation by neurons and astrocytes. ATP triggers the recruitment of microglial protrusions and is converted by the microglial ATP/ADP hydrolysing ectoenzyme CD39 into AMP; AMP is then converted into adenosine by CD73, which is expressed on microglia as well as other brain cells. Microglial sensing of ATP, the ensuing microglia-dependent production of adenosine, and the adenosine-mediated suppression of neuronal responses via the adenosine receptor A.sub.1R are essential for the regulation of neuronal activity and animal behaviour. Our findings suggest that this microglia-driven negative feedback mechanism operates similarly to inhibitory neurons and is essential for protecting the brain from excessive activation in health and disease. Microglia, the brain's immune cells, suppress neuronal activity in response to synaptic ATP release and alter behavioural responses in mice., Author(s): Ana Badimon [sup.1] [sup.2] [sup.3] , Hayley J. Strasburger [sup.1] [sup.2] [sup.3] , Pinar Ayata [sup.1] [sup.2] [sup.3] [sup.4] , Xinhong Chen [sup.5] , Aditya Nair [sup.5] , Ako [...]

Sensory experience in early postnatal life, during so-called critical periods, restructures neural circuitry to enhance information processing.sup.1. Why the cortex is susceptible to sensory instruction in early life and why this susceptibility wanes with age are unclear. Here we define a developmentally restricted engagement of inhibitory circuitry that shapes localized dendritic activity and is needed for vision to drive the emergence of binocular visual responses in the mouse primary visual cortex. We find that at the peak of the critical period for binocular plasticity, acetylcholine released from the basal forebrain during periods of heightened arousal directly excites somatostatin (SST)-expressing interneurons. Their inhibition of pyramidal cell dendrites and of fast-spiking, parvalbumin-expressing interneurons enhances branch-specific dendritic responses and somatic spike rates within pyramidal cells. By adulthood, this cholinergic sensitivity is lost, and compartmentalized dendritic responses are absent but can be re-instated by optogenetic activation of SST cells. Conversely, suppressing SST cell activity during the critical period prevents the normal development of binocular receptive fields by impairing the maturation of ipsilateral eye inputs. This transient cholinergic modulation of SST cells, therefore, seems to orchestrate two features of neural plasticity--somatic disinhibition and compartmentalized dendritic spiking. Loss of this modulation may contribute to critical period closure. A transient circuit that links cholinergic neuromodulation and inhibition is responsible for the dendritic compartmentalization of evoked responses in the mouse visual cortex during the critical period of robust plasticity., Author(s): Courtney E. Yaeger [sup.1] , Dario L. Ringach [sup.1] [sup.2] , Joshua T. Trachtenberg [sup.1] Author Affiliations: (1) Department of Neurobiology, David Geffen School of Medicine at UCLA, Los [...]

Sounds can arise from the environment and also predictably from many of our own movements, such as vocalizing, walking, or playing music. The capacity to anticipate these movement-related (reafferent) sounds and distinguish them from environmental sounds is essential for normal hearing.sup.1,2, but the neural circuits that learn to anticipate the often arbitrary and changeable sounds that result from our movements remain largely unknown. Here we developed an acoustic virtual reality (aVR) system in which a mouse learned to associate a novel sound with its locomotor movements, allowing us to identify the neural circuit mechanisms that learn to suppress reafferent sounds and to probe the behavioural consequences of this predictable sensorimotor experience. We found that aVR experience gradually and selectively suppressed auditory cortical responses to the reafferent frequency, in part by strengthening motor cortical activation of auditory cortical inhibitory neurons that respond to the reafferent tone. This plasticity is behaviourally adaptive, as aVR-experienced mice showed an enhanced ability to detect non-reafferent tones during movement. Together, these findings describe a dynamic sensory filter that involves motor cortical inputs to the auditory cortex that can be shaped by experience to selectively suppress the predictable acoustic consequences of movement.Training of mice to associate a particular sound frequency with locomotion results in selective suppression of cortical responses to that frequency during movement, consistent with a motor-dependent form of auditory cortical plasticity., Author(s): David M. Schneider [sup.1] [sup.2] , Janani Sundararajan [sup.1] , Richard Mooney [sup.1] Author Affiliations:(1) Department of Neurobiology, Duke University School of Medicine, Durham, USA(2) Center for Neural Science, [...]

Sleep is a fundamental biological process observed widely in the animal kingdom, but the neural circuits generating sleep remain poorly understood. Understanding the brain mechanisms controlling sleep requires the identification of key neurons in the control circuits and mapping of their synaptic connections. Technical innovations over the past decade have greatly facilitated dissection of the sleep circuits. This has set the stage for understanding how a variety of environmental and physiological factors influence sleep. The ability to initiate and terminate sleep on command will also help us to elucidate its functions within and beyond the brain., Author(s): Franz Weber [1]; Yang Dan (corresponding author) [1] Sleep is a seemingly unproductive behavioural state that takes up a large proportion of our lives, but insufficient sleep can profoundly [...]

Here, the circuits underlying the motivational or rewarding component to aggression are deconstructed, showing that an inhibitory projection from the basal forebrain to the lateral habenula bi-directionally controls this aspect of aggression. Aggression as its own reward The brain areas responsible for initiating aggressive behaviour have been identified, but little is known about the systems responsible for establishing a motivational or rewarding component to aggression. Here, Scott Russo and colleagues deconstruct the circuits underlying reward processing as it relates to aggression. They show that an inhibitory projection from the basal forebrain to the lateral habenula controls this aspect of aggression bi-directionally. This work could pave the way for the identification of targets for therapeutics designed to treat aggression and aggression-related neuropsychiatric disorders Maladaptive aggressive behaviour is associated with a number of neuropsychiatric disorders.sup.1 and is thought to result partly from the inappropriate activation of brain reward systems in response to aggressive or violent social stimuli.sup.2. Nuclei within the ventromedial hypothalamus.sup.3,4,5, extended amygdala.sup.6 and limbic.sup.7 circuits are known to encode initiation of aggression; however, little is known about the neural mechanisms that directly modulate the motivational component of aggressive behaviour.sup.8. Here we established a mouse model to measure the valence of aggressive inter-male social interaction with a smaller subordinate intruder as reinforcement for the development of conditioned place preference (CPP). Aggressors develop a CPP, whereas non-aggressors develop a conditioned place aversion to the intruder-paired context. Furthermore, we identify a functional GABAergic projection from the basal forebrain (BF) to the lateral habenula (lHb) that bi-directionally controls the valence of aggressive interactions. Circuit-specific silencing of GABAergic BF-lHb terminals of aggressors with halorhodopsin (NpHR3.0) increases lHb neuronal firing and abolishes CPP to the intruder-paired context. Activation of GABAergic BF-lHb terminals of non-aggressors with channelrhodopsin (ChR2) decreases lHb neuronal firing and promotes CPP to the intruder-paired context. Finally, we show that altering inhibitory transmission at BF-lHb terminals does not control the initiation of aggressive behaviour. These results demonstrate that the BF-lHb circuit has a critical role in regulating the valence of inter-male aggressive behaviour and provide novel mechanistic insight into the neural circuits modulating aggression reward processing., Author(s): Sam A. Golden [sup.1] [sup.2] , Mitra Heshmati [sup.1] [sup.2] , Meghan Flanigan [sup.1] [sup.2] , Daniel J. Christoffel [sup.3] , Kevin Guise [sup.1] [sup.2] , Madeline L. Pfau [...]

Survival in threatening situations depends on the selection and rapid execution of an appropriate active or passive defensive response, yet the underlying brain circuitry is not understood. Here we use circuit-based optogenetic, in vivo and in vitro electrophysiological, and neuroanatomical tracing methods to define midbrain periaqueductal grey circuits for specific defensive behaviours. We identify an inhibitory pathway from the central nucleus of the amygdala to the ventrolateral periaqueductal grey that produces freezing by disinhibition of ventrolateral periaqueductal grey excitatory outputs to pre-motor targets in the magnocellular nucleus of the medulla. In addition, we provide evidence for anatomical and functional interaction of this freezing pathway with long-range and local circuits mediating flight. Our data define the neuronal circuitry underlying the execution of freezing, an evolutionarily conserved defensive behaviour, which is expressed by many species including fish, rodents and primates. In humans, dysregulation of this 'survival circuit' has been implicated in anxiety-related disorders., Threatening situations, such as the presence of a predator or exposure to stimuli predicting imminent or perceived danger, evoke an evolutionarily conserved brain state, fear, which triggers defensive behaviours to [...]

Spatial navigation requires information about the relationship between current and future positions. The activity of hippocampal neurons appears to reflect such a relationship, representing not only instantaneous position but also the path towards a goal location. However, how the hippocampus obtains information about goal direction is poorly understood. Here we report a prefrontal-thalamic neural circuit that is required for hippocampal representation of routes or trajectories through the environment. Trajectory-dependent firing was observed in medial prefrontal cortex, the nucleus reuniens of the thalamus, and the CA1 region of the hippocampus in rats. Lesioning or optogenetic silencing of the nucleus reuniens substantially reduced trajectory-dependent CA1 firing. Trajectory-dependent activity was almost absent in CA3, which does not receive nucleus reuniens input. The data suggest that projections from medial prefrontal cortex, via the nucleus reuniens, are crucial for representation of the future path during goal-directed behaviour and point to the thalamus as a key node in networks for long-range communication between cortical regions involved in navigation., Hippocampal place cells are part of an allocentric representation of local space that allows animals to navigate to desired locations (1,2). Place cells provide accurate information about current location, but [...]

Many animals navigate using a combination of visual landmarks and path integration. In mammalian brains, head direction cells integrate these two streams of information by representing an animal's heading relative to landmarks, yet maintaining their directional tuning in darkness based on self-motion cues. Here we use two-photon calcium imaging in head-fixed Drosophila melanogaster walking on a ball in a virtual reality arena to demonstrate that landmark-based orientation and angular path integration are combined in the population responses of neurons whose dendrites tile the ellipsoid body, a toroidal structure in the centre of the fly brain. The neural population encodes the fly's azimuth relative to its environment, tracking visual landmarks when available and relying on self-motion cues in darkness. When both visual and self-motion cues are absent, a representation of the animal's orientation is maintained in this network through persistent activity, a potential substrate for short-term memory. Several features of the population dynamics of these neurons and their circular anatomical arrangement are suggestive of ring attractors, network structures that have been proposed to support the function of navigational brain circuits., Author(s): Johannes D. Seelig [1]; Vivek Jayaraman (corresponding author) [1] Visual landmarks can provide animals with a reliable indicator of their whereabouts [1]. In the absence of such cues, many [...]

Author(s): Praneeth Namburi [1, 2]; Anna Beyeler [1]; Suzuko Yorozu [3]; Gwendolyn G. Calhoon [1]; Sarah A. Halbert [1, 4]; Romy Wichmann [1]; Stephanie S. Holden [1, 5]; Kim L. [...]

Models derived from human pluripotent stem cells that accurately recapitulate neural development in vitro and allow for the generation of specific neuronal subtypes are of major interest to the stem cell and biomedical community. Notch signalling, particularly through the Notch effector HES5, is a major pathway critical for the onset and maintenance of neural progenitor cells in the embryonic and adult nervous system (1-3). Here we report the transcriptional and epigenomic analysis of six consecutive neural progenitor cell stages derived from a HES5::eGFP reporter human embryonic stem cell line (4). Using this system, we aimed to model cell-fate decisions including specification, expansion and patterning during the ontogeny of cortical neural stem and progenitor cells. In order to dissect regulatory mechanisms that orchestrate the stage-specific differentiation process, we developed a computational framework to infer key regulators of each cell-state transition based on the progressive remodelling of the epigenetic landscape and then validated these through a pooled short hairpin RNA screen. We were also able to refine our previous observations on epigenetic priming at transcription factor binding sites and suggest here that they are mediated by combinations of core and stage-specific factors. Taken together, we demonstrate the utility of our system and outline a general framework, not limited to the context of the neural lineage, to dissect regulatory circuits of differentiation., We used the human embryonic stem (ES) cell line WA9 (also known as H9) expressing GFP under the HES5 promoter (4) to isolate defined neural progenitor populations of neuroepithelial (NE), [...]

Accumulating evidence points to cortical oscillations as a mechanism for mediating interactions among functionally specialized neurons in distributed brain circuits (1-6). A brain function that may use such interactions is declarative memory--that is, memory that can be consciously recalled, such as episodes and facts. Declarative memory is enabled by circuits in the entorhinal cortex that interface the hippocampus with the neocortex (7,8). During encoding and retrieval of declarative memories, entorhinal and hippocampal circuits are thought to interact via theta and gamma oscillations (4,6,8), which in awake rodents predominate frequency spectra in both regions (9-12). In favour of this idea, theta-gamma coupling has been observed between entorhinal cortex and hippocampus under steady-state conditions in well-trained rats (12); however, the relationship between interregional coupling and memory formation remains poorly understood. Here we show, by multisite recording at successive stages of associative learning, that the coherence of firing patterns in directly-connected entorhinal-hippocampus circuits evolves as rats learn to use an odour cue to guide navigational behaviour, and that such coherence is invariably linked to the development of ensemble representations for unique trial outcomes in each area. Entorhinal-hippocampal coupling was observed specifically in the 20-40-hertz frequency band and specifically between the distal part of hippocampal area CA1 and the lateral part of entorhinal cortex, the subfields that receive the predominant olfactory input to the hippocampal region (13). Collectively, the results identify 20-40-hertz oscillations as a mechanism for synchronizing evolving representations in dispersed neural circuits during encoding and retrieval of olfactory-spatial associative memory., Neural activity was recorded from entorhinal cortex (EC) and CA1 of 17 rats trained to solve a simplified version of an odour-place association task thought to depend on interfacing of [...]

How does the mammalian retina detect motion? This classic problem in visual neuroscience has remained unsolved for 50 years. In search of clues, here we reconstruct Off-type starburst amacrine cells (SACs) and bipolar cells (BCs) in serial electron microscopic images with help from EyeWire, an online community of 'citizen neuroscientists'. On the basis of quantitative analyses of contact area and branch depth in the retina, we find evidence that one BC type prefers to wire with a SAC dendrite near the SAC soma, whereas another BC type prefers to wire far from the soma. The near type is known to lag the far type in time of visual response. A mathematical model shows how such 'space-time wiring specificity' could endow SAC dendrites with receptive fields that are oriented in space-time and therefore respond selectively to stimuli that move in the outward direction from the soma., Compared to cognitive functions such as language, the visual detection of motion may seem trivial, yet the underlying neural mechanisms have remained elusive for half a century (1,2). Some retinal [...]

Astrocytes, the most abundant cells in the central nervous system, promote synapse formation and help to refine neural connectivity. Although they are allocated to spatially distinct regional domains during development, it is unknown whether region-restricted astrocytes are functionally heterogeneous. Here we show that postnatal spinal cord astrocytes express several region-specific genes, and that ventral astrocyte-encoded semaphorin 3a (Sema3a) is required for proper motor neuron and sensory neuron circuit organization. Loss of astrocyte-encoded Sema3a leads to dysregulated a-motor neuron axon initial segment orientation, markedly abnormal synaptic inputs, and selective death of α- but not of adjacent γ-motor neurons. In addition, a subset of TrkA1 sensory afferents projects to ectopic ventral positions. These findings demonstrate that stable maintenance of a positional cue by developing astrocytes influences multiple aspects of sensorimotor circuit formation. More generally, they suggest that regional astrocyte heterogeneity may help to coordinate postnatal neural circuit refinement., Developing neural circuits must form and maintain appropriate regional connections in a rapidly expanding central nervous system (CNS). Although astrocytes (AS) are increasingly recognized as general regulators of synapse formation [...]

In the mammalian cerebral cortex, neural responses are highly variable during spontaneous activity and sensory stimulation. To explain this variability, the cortex of alert animals has been proposed to be in an asynchronous high-conductance state in which irregular spiking arises from the convergence of large numbers of uncorrelated excitatory and inhibitory inputs onto individual neurons (1-4). Signatures of this state are that a neuron's membrane potential ([V.sub.m]) hovers just below spike threshold, and its aggregate synaptic input is nearly Gaussian, arising from many uncorrelated inputs (1-4). Alternatively, irregular spiking could arise from infrequent correlated input events that elicit large fluctuations in [V.sub.m] (refs 5,6). To distinguish between these hypotheses, we developed a technique to perform whole-cell [V.sub.m] measurements from the cortex of behaving monkeys, focusing on primary visual cortex (V1) of monkeys performing a visual fixation task. Here we show that, contrary to the predictions of an asynchronous state, mean [V.sub.m] during fixation was far from threshold (14 mV) and spiking was triggered by occasional large spontaneous fluctuations. Distributions of [V.sub.m] values were skewed beyond that expected for a range of Gaussian input (6,7), but were consistent with synaptic input arising from infrequent correlated events (5,6). Furthermore, spontaneous fluctuations in [V.sub.m] were correlated with the surrounding network activity, as reflected in simultaneously recorded nearby local field potential. Visual stimulation, however, led to responses more consistent with an asynchronous state: mean [V.sub.m] approached threshold, fluctuations became more Gaussian, and correlations between single neurons and the surrounding network were disrupted. These observations show that sensory drive can shift a common cortical circuitry from a synchronous to an asynchronous state., Cortical neurons show variable activity even after efforts are taken to fix temporal variations in sensory stimuli and attentional state (8). This ongoing activity affects stimulus encoding and synaptic plasticity [...]

How specific features in the environment are represented within the brain is an important unanswered question in neuroscience. A subset of retinal neurons, called direction-selective ganglion cells (DSGCs), are specialized for detecting motion along specific axes of the visual field (1). Despite extensive study of the retinal circuitry that endows DSGCs with their unique tuning properties (2,3), their downstream circuitry in the brain and thus their contribution to visual processing has remained unclear. In mice, several different types of DSGCs connect to the dorsal lateral geniculate nucleus (dLGN) (4-6), the visual thalamic structure that harbours cortical relay neurons. Whether direction-selective information computed at the level of the retina is routed to cortical circuits and integrated with other visual channels, however, is unknown. Here we show that there is a di-synaptic circuit linking DSGCs with the superficial layers of the primary visual cortex (V1) by using viral trans-synaptic circuit mapping (7,8) and functional imaging of visually driven calcium signals in thalamocortical axons. This circuit pools information from several types of DSGCs, converges in a specialized subdivision of the dLGN, and delivers direction-tuned and orientation-tuned signals to superficial V1. Notably, this circuit is anatomically segregated from the retino-geniculo-cortical pathway carrying non-direction-tuned visual information to deeper layers of V1, such as layer 4. Thus, the mouse harbours several functionally specialized, parallel retino-geniculo-cortical pathways, one of which originates with retinal DSGCs and delivers direction- and orientation-tuned information specifically to the superficial layers of the primary visual cortex. These data provide evidence that direction and orientation selectivity of some V1 neurons may be influenced by the activation of DSGCs., Visual perception involves the activity of neurons in the cerebral cortex. The most direct route for visual information to reach the cortex is via the 'retino-geniculo-cortical pathway' consisting of retinal [...]

Neuromodulatory control by oxytocin is essential to a wide range of social (1,2), parental (3) and stress-related behaviours (4). Autism spectrum disorders (ASD) are associated with deficiencies in oxytocin levels5 and with genetic alterations of the oxytocin receptor (OXTR) (6). Thirty years ago, Muhlethaler et al. (7) found that oxytocin increases the firing of inhibitory hippocampal neurons, but it remains unclear how elevated inhibition could account for the ability of oxytocin to improve information processing in the brain. Here we describe in mammalian hippocampus a simple yet powerful mechanism by which oxytocin enhances cortical information transfer while simultaneously lowering background activity, thus greatly improving the signal-to-noise ratio. Increased fast-spiking interneuron activity not only suppresses spontaneous pyramidal cell firing, but also enhances the fidelity of spike transmission and sharpens spike timing. Use-dependent depression at the fast-spiking interneuron-pyramidal cell synapse is both necessary and sufficient for the enhanced spike throughput. We show the generality of this novel circuit mechanism by activation of fast-spiking interneurons with cholecystokinin or channelrhodopsin-2. This provides insight into how a diffusely delivered neuromodulator can improve the performance of neural circuitry that requires synapse specificity and millisecond precision., The CA1 region of hippocampus receives potent excitatory input from neighbouring area CA3 through the Schaffer Collateral (SC) pathway. Activation of SC axons evokes a monosynaptic excitatory postsynaptic potential (EPSP) [...]

Neurons in the prefrontal cortex exhibit diverse behavioural Correlates (1-4), an observation that has been attributed to cell-type diversity. To link identified neuron types with network and behavioural functions, we recorded from the two largest genetically defined inhibitory interneuron classes, the perisomatically targeting parvalbumin (PV) and the dendritically targeting somatostatin (SOM) neurons (5-8) in anterior cingulate cortex of mice performing a reward foraging task. Here we show that PV and a subtype of SOM neurons form functionally homogeneous populations showing a double dissociation between both their inhibitory effects and behavioural correlates. Out of several events pertaining to behaviour, a subtype of SOM neurons selectively responded at reward approach, whereas PV neurons responded at reward leaving and encoded preceding stay duration. These behavioural correlates of PV and SOM neurons defined a behavioural epoch and a decision variable important for foraging (whether to stay or to leave), a crucial function attributed to the anterior cingulate cortex (9-11). Furthermore, PV neurons could fire in millisecond synchrony, exerting fast and powerful inhibition on principal cell firing, whereas the inhibitory effect of SOM neurons on firing output was weak and more variable, consistent with the idea that they respectively control the outputs of, and inputs to, principal neurons (12-16). These results suggest a connection between the circuit-level function of different interneuron types in regulating the flow of information and the behavioural functions served by the cortical circuits. Moreover, these observations bolster the hope that functional response diversity during behaviour can in part be explained by cell-type diversity., To investigate whether distinct interneuron types can encode specific behavioural variables we recorded the activity of inhibitory neurons expressing parvalbumin and somatostatin markers (Supplementary Fig. 1a). PV basket cells are [...]

The activity of the cerebral cortex is thought to depend on the precise relationship between synaptic excitation and inhibition (1-4). In the visual cortex, in particular, intracellular measurements have related [...]

The response of cortical neurons to a sensory stimulus is modulated by the context. In the visual cortex, for example, stimulation of a pyramidal cell's receptive-field surround can attenuate the [...]

Researchers seeking to understand the brain want big data. And they are getting them. Just as geneticists have moved from genes to genomes to the interacting network of factors that [...]

The ability to process relevant stimuli selectively is a fundamental function of the primate visual system. The best-understood correlate of this function is the enhanced response of neurons in the [...]

Adult neurogenesis arises from neural stem cells within specialized niches (1-3). Neuronal activity and experience, presumably acting on this local niche, regulate multiple stages of adult neurogenesis, from neural progenitor [...]

Brain circuits process information through specialized neuronal subclasses interacting within a network. Revealing their interplay requires activating specific cells while monitoring others in a functioning circuit. Here we use a new platform for two-way light-based circuit interrogation in visual cortex in vivo to show the computational implications of modulating different subclasses of inhibitory neurons during sensory processing. We find that soma-targeting, parvalbumin-expressing (PV) neurons principally divide responses but preserve stimulus selectivity, whereas dendrite-targeting, somatostatin-expressing (SOM) neurons principally subtract from excitatory responses and sharpen selectivity. Visualized in vivo cell-attached recordings show that division by PV neurons alters response gain, whereas subtraction by SOM neurons shifts response levels. Finally, stimulating identified neurons while scanning many target cells reveals that single PV and SOM neurons functionally impact only specific subsets of neurons in their projection fields. These findings provide direct evidence that inhibitory neuronal subclasses have distinct and complementary roles in cortical computations. Use of a two-way optical system to activate subclasses of inhibitory neurons, while simultaneously monitoring responses in target cells within cortical circuits in vivo, reveals that parvalbumin-expressing and somatostatin-expressing neurons exert distinct effects on cellular responses across the network. Class distinction in cortical interneurons Cortical networks consist of a range of neuronal cells, including multiple classes of inhibitory interneurons. Intracortical inhibition is essential for normal brain function, but little is known about the specific roles of the neuronal subtypes. Two independent papers from the groups of Mriganka Sur and Yang Dan explore the functional consequences of activating different classes of interneurons in the mouse visual cortex. Using a variety of techniques, both papers demonstrate that activating parvalbumin-expressing versus other classes of interneurons has distinct effects on the response properties of individual excitatory cells, as well as on populations of these cells. The paper from Dan's group also finds effects on visual behaviour in awake mice., Author(s): Nathan R. Wilson [sup.1] , Caroline A. Runyan [sup.1] , Forea L. Wang [sup.1] , Mriganka Sur [sup.1] Author Affiliations: (1) Department of Brain and Cognitive Sciences, Picower Institute [...]

The posterior parietal cortex (PPC) has an important role in many cognitive behaviours; however, the neural circuit dynamics underlying PPC function are not well understood. Here we optically imaged the spatial and temporal activity patterns of neuronal populations in mice performing a PPC-dependent task that combined a perceptual decision and memory-guided navigation in a virtual environment. Individual neurons had transient activation staggered relative to one another in time, forming a sequence of neuronal activation spanning the entire length of a task trial. Distinct sequences of neurons were triggered on trials with opposite behavioural choices and defined divergent, choice-specific trajectories through a state space of neuronal population activity. Cells participating in the different sequences and at distinct time points in the task were anatomically intermixed over microcircuit length scales (, In real-world tasks, decision-making and working memory often occur in the context of other complex behaviours, including spatial navigation. For example, when driving through a city towards a destination, sensory [...]

Spatial asymmetries in neural connectivity have an important role in creating basic building blocks of neuronal processing (1,2). A key circuit module of directionally selective (DS) retinal ganglion cells is a spatially asymmetric inhibitory input from starburst amacrine cells (3-5). It is not known how and when this circuit asymmetry is established during development. Here we photostimulate mouse starburst cells targeted with channelrhodopsin-2 (refs 6-8) while recording from a single genetically labelled type of DS cell (9,10). We follow the spatial distribution of synaptic strengths between starburst and DS cells during early postnatal development before these neurons can respond to a physiological light stimulus, and confirm connectivity by monosynaptically restricted trans-synaptic rabies viral tracing. We show that asymmetry develops rapidly over a 2-day period through an intermediate state in which random or symmetric synaptic connections have been established. The development of asymmetry involves the spatially selective reorganization of inhibitory synaptic inputs. Intriguingly, the spatial distribution of excitatory synaptic inputs from starburst cells is significantly more symmetric than that of the inhibitory inputs at the end of this developmental period. Our work demonstrates a rapid developmental switch from a symmetric to asymmetric input distribution for inhibition in the neural circuit of a principal cell., DS retinal ganglion cells respond to movement in a 'preferred' direction with robust spiking, but show minimal response to movement in the opposite, or 'null', direction (2,11-13). DS cells receive [...]

The mammalian cochlea is innervated by two classes of sensory neurons. Type I neurons make up 90-95% of the cochlear nerve and contact single inner hair cells to provide acoustic analysis as we know it. In contrast, the far less numerous type II neurons arborize extensively among outer hair cells (OHCs) (1,2) and supporting cells (3,4). Their scarcity and smaller calibre axons have made them the subject of much speculation, but little experimental progress for the past 50 years. Here we record from type II fibres near their terminal arbors under OHCs to show that they receive excitatory glutamatergic synaptic input. The type II peripheral arbor conducts action potentials, but the small and infrequent glutamatergic excitation indicates a requirement for strong acoustic stimulation. Furthermore, we show that type II neurons are excited by ATP. Exogenous ATP depolarized type II neurons, both directly and by evoking glutamatergic synaptic input (5). These results prove that type II neurons function as cochlear afferents, and can be modulated by ATP. The lesser magnitude of synaptic drive dictates a fundamentally different role in auditory signalling from that of type I afferents., The organ of Corti was dissected from the apical turn of postnatal rat cochleas (postnatal days (P)5-19) and secured in a recording chamber. A few OHCs were removed by aspiration [...]

At first glance, Jeff Lichtman seems to be hanging long strips of sticky tape from the walls of his Harvard lab. The tape flutters in the breeze from the air-conditioner. [...]

Author(s): Paolo Capelli [1, 2]; Chiara Pivetta [1, 2]; Maria Soledad Esposito [1, 2]; Silvia Arber (corresponding author) [1, 2] Locomotion is a universal behaviour that provides animals with the [...]

Author(s): Hojoon Lee [1, 2]; Lindsey J. Macpherson [1, 2]; Camilo A. Parada [1, 2]; Charles S. Zuker (corresponding author) [1, 2]; Nicholas J. P. Ryba [3] In mammals, taste [...]

The prefrontal cortex is a critical neuroanatomical hub for controlling motivated behaviours across mammalian species. In addition to intra-cortical connectivity, prefrontal projection neurons innervate subcortical structures that contribute to reward-seeking behaviours, such as the ventral striatum and midline thalamus. While connectivity among these structures contributes to appetitive behaviours, how projection-specific prefrontal neurons encode reward-relevant information to guide reward seeking is unknown. Here we use in vivo two-photon calcium imaging to monitor the activity of dorsomedial prefrontal neurons in mice during an appetitive Pavlovian conditioning task. At the population level, these neurons display diverse activity patterns during the presentation of reward-predictive cues. However, recordings from prefrontal neurons with resolved projection targets reveal that individual corticostriatal neurons show response tuning to reward-predictive cues, such that excitatory cue responses are amplified across learning. By contrast, corticothalamic neurons gradually develop new, primarily inhibitory responses to reward-predictive cues across learning. Furthermore, bidirectional optogenetic manipulation of these neurons reveals that stimulation of corticostriatal neurons promotes conditioned reward-seeking behaviour after learning, while activity in corticothalamic neurons suppresses both the acquisition and expression of conditioned reward seeking. These data show how prefrontal circuitry can dynamically control reward-seeking behaviour through the opposing activities of projection-specific cell populations., Author(s): James M. Otis [1]; Vijay M. K. Namboodiri [1, 2]; Ana M. Matan [1]; Elisa S. Voets [1]; Emily P. Mohorn [1]; Oksana Kosyk [1]; Jenna A. McHenry [1]; [...]

Author(s): Jonathan P. Fadok [1]; Sabine Krabbe [1]; Milica Markovic [1, 2]; Julien Courtin [1]; Chun Xu [1]; Lema Massi [1]; Paolo Botta [1, 2]; Kristine Bylund [1]; Christian Mller [...]

High-speed link in the brain inhibits movement. High-speed link in the brain inhibits movement., Author Affiliations: Neurons in the brain conduct messages that can control or stop movement. Credit: PR. S. BRION -- CNRI/SPL Micrograph of brain cells, coloured blue and purple. A neural [...]

It is possible to successfully predict cat neuronal signalling with a model derived to account for human psychophysical performance. This research, which involved recording unit activity from cortical area A2 in anaesthetized cats, established that neurons accurately signal the elevations of broadband sounds localized accurately by humans. There is strong evidence to support the view that neuronal elevation sensitivity in cats and spatial hearing in humans respond to similar computational principles.

Author(s): Josue Haubrich [1]; Karim Nader (corresponding author) [1] Memories enable people to recollect events from the past to both plan for the future and properly guide their behavior in [...]

Author(s): Zhiguo Ma [1]; Tobias Stork [1]; Dwight E. Bergles [2]; Marc R. Freeman (corresponding author) [1] Astrocytes associate with synapses throughout the brain and express receptors for neurotransmitters that [...]

Sound localization in mammals and birds uses coincidence-detector neurons in the auditory brainstem to map interaural time differences. A new study uses a simple computational model to simulate the known geometry and electrophysiology of the cells to show that dendrites are able to improve their coincidence detection properties.

The population coding in a small network underlying the leech local bend is reported. A complete set of sensory inputs to the network were monitored and manipulated. The population vector was found to correlate with bend direction, linking a proposed algorithm for neural population coding with synaptic and network mechanisms.

Encoding of odor occurs in the temporal sequence of neural assemblies which are non-randomly updated during each oscillatory response pattern. Oscillatory synchronizations recruit neurons in an oscillating assembly in a stimulus-specific manner. The phase of the active neuron firing fails to contain any information about the stimulus. Oscillations help in the combinatorial neural coding of odor in time and space, with the information stored in the temporal firing pattern of the neuron groups.

The stomatogastric ganglion cells in the lobster receive fast cyclic AMP signals due to synaptic release of endogenous neuromodulators in an intact neural circuit. This produces rapid changes in the configuration of the neural circuitry. The prolonged stimulation of the cyclic AMP leads to its diffusion throughout the cell body. This provides the neuromodulatory signals a mechanism for the coordination of various functions within the different regions of the neuron.

Previous research has shown that synaptic transmission is terminated by diffusion and reuptake of neurotransmitters from the synaptic cleft. The reuptake of glutamate regulates the concentration of extracellular glutamate and prevents neurotoxicity. Using voltage clamping with a pH-sensitive fluorescent dye to monitor electrical current and pH changes of a flux of glutamate mediated by transporter EAAT3, it was discovered that three sodium ions and one proton are cotransported with each glutamate ion into the cell while a single potassium ion is transported out. The results suggest that the transporter EAAT3 could continue removing glutamate if a transmembrane glutamate concentrate gradient exceeding 10 is maintained.

Previous research has shown that synchronous neuronal oscillations between 30 and 70 Hz occur in the cortex of most higher organisms. Also known as gamma oscillations, the precise mechanics of such a phenomenon has been difficult to ascertain given their long periods of phase lags. However, a model incorporating the properties of excitatory pyramidal cells and inhibitory interneurons has been able to predict the generation of gamma oscillations. The model monitors the production of pairs of spikes in rapid succession to determine the generation of gamma oscillations.

The aggregation of neuregulins at synaptic sites and the remnants of neuregulins at the synaptic sites when nerve and muscle cells are absent is demonstrated using antibodies. The erbB3 mRNA and the erbB2 mRNA with less erbB4 mRNA are found in the C2 muscle cells. Tyrosine phosphorylation in erbB2 and erbB3 is stimulated by neuregulins, revealing that erbB2 and erbB3 mediate neuregulin signalling in skeletal muscles.

Two rhesus monkeys were trained on a compound oculometer delayed-response task trials, in some of which eye jerks were directed toward the stimulus, to find the neuronal activity involved in the dorsolateral prefrontal cortex. In some cases, the saccades were diverted away from the stimulus, and the monkeys learnt to avoid looking at the signal-inducing visual cues. The inability to do so was noted in those suffering from large frontal lobe lesions. Stimulus-coding neurons influence reaction suppression, which is indicated when the neuron with complex firing patterns is affected by the direction of the reaction and the location of the stimulus.

An investigation was conducted to elucidate the neurocircuitry of the mossy fibre pathway of the hippocampus. This pathway contains glutamate as a neurotransmitter as well as the opioid peptide dynorphin. The results showed that activation of mossy fibres which leads to the transmission of glutamate also generates a long-lasting inhibition of neighboring mossy fiber synapses by a presynaptic action of synaptically released dynorphin. This presynaptic inhibition was more pronounced in synapses expressing long-term potentiation. The results indicate that dynorphin has a physiological role in glutamatergic mossy fiber synapses.

Author(s): Hannah Stower [sup.1] Author Affiliations: (1) Nature Medicine, Nature 568 , 493-498 (2019) Neural activity in the cortex can be translated into speech using a synthetic device. The loss [...]

Author(s): Niv Scott [1]; Matthias Prigge [1]; Ofer Yizhar (corresponding author) [1]; Tali Kimchi (corresponding author) [1] It is commonly assumed, but has rarely been demonstrated [1, 2], that sex [...]

Anyone who wears glasses knows the experience of putting them on. What was fuzzy, blurry and ill-defined suddenly snaps into focus. On page 745 of this issue, Sobolevsky et al. [...]