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Safety assessment and threat evaluation are crucial for animals to live and survive in the wilderness. However, neural circuits underlying safety assessment and their transformation to mediate flexibility of fear-induced defensive behaviors remain largely unknown. Here, we report that distinct neuronal populations in mouse anterior cingulate cortex (ACC) encode safety status by selectively responding under different contexts of auditory threats, with one preferably activated when an animal staysing in a self-deemed safe zone and another specifically activated in more dangerous environmental settings that led to escape behavior. The safety-responding neurons preferentially target the zona incerta (ZI), which suppresses the superior colliculus (SC) via its GABAergic projection, while the danger-responding neurons preferentially target and excite SC. These distinct corticofugal pathways antagonistically modulate SC responses to threat, resulting in context-dependent expression of fear reactions. Thus, ACC serves as a critical node to encode safety/danger assessment and mediate behavioral flexibility through differential top-down circuits., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Extracting the valence of environmental cues is critical for animals' survival. How valence in sensory signals is encoded and transformed to produce distinct behavioral responses remains not well understood. Here, we report that the mouse pontine central gray (PCG) contributes to encoding both negative and positive valences. PCG glutamatergic neurons were activated selectively by aversive, but not reward, stimuli, whereas its GABAergic neurons were preferentially activated by reward signals. The optogenetic activation of these two populations resulted in avoidance and preference behavior, respectively, and was sufficient to induce conditioned place aversion/preference. Suppression of them reduced sensory-induced aversive and appetitive behaviors, respectively. These two functionally opponent populations, receiving a broad range of inputs from overlapping yet distinct sources, broadcast valence-specific information to a distributed brain network with distinguishable downstream effectors. Thus, PCG serves as a critical hub to process positive and negative valences of incoming sensory signals and drive valence-specific behaviors with distinct circuits., Competing Interests: Declaration of interests I.R.W. is a consultant for Monosynaptix, LLC, advising on the design of neuroscientific experiments., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In the mammalian visual system, information from the retina streams into parallel bottom-up pathways. It remains unclear how these pathways interact to contribute to contextual modulation of visual cortical processing. By optogenetic inactivation and activation of mouse lateral posterior nucleus (LP) of thalamus, a homolog of pulvinar, or its projection to primary visual cortex (V1), we found that LP contributes to surround suppression of layer (L) 2/3 responses in V1 by driving L1 inhibitory neurons. This results in subtractive suppression of visual responses and an overall enhancement of orientation, direction, spatial, and size selectivity. Neurons in V1-projecting LP regions receive bottom-up input from the superior colliculus (SC) and respond preferably to non-patterned visual noise. The noise-dependent LP activity allows V1 to "cancel" noise effects and maintain its orientation selectivity under varying noise background. Thus, the retina-SC-LP-V1 pathway forms a differential circuit with the canonical retino-geniculate pathway to achieve context-dependent sharpening of visual representations., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Emotions evoked by environmental cues are important for animal survival and life quality. However, neural circuits responsible for transforming sensory signals to aversive emotion and behavioral avoidance remain unclear. Here, we found that medial septum (MS) mediates aversion induced by both auditory and somatosensory stimuli. Ablation of glutamatergic or GABAergic MS neurons results in impaired or strengthened aversion, respectively. Optogenetic activation of the two cell types results in place avoidance and preference, respectively. Cell-type-specific screening reveals that glutamatergic MS projections to the lateral habenula (LHb) are responsible for the induction of aversion, which can be antagonized by GABAergic MS projections to LHb. Additionally, the sensory-induced place avoidance is facilitated by enhanced locomotion mediated by glutamatergic MS projections to the preoptic area. Thus, MS can transmit innately aversive signals via a bottom-up multimodal sensory pathway and produce concurrent emotional and motional effects, allowing animals to efficiently avoid unfavorable environments., (Copyright © 2018 Elsevier Inc. All rights reserved.)

In the mammalian brain, auditory information is known to be processed along a central ascending pathway leading to auditory cortex (AC). Whether there exist any major pathways beyond this canonical auditory neuraxis remains unclear. In awake mice, we found that auditory responses in entorhinal cortex (EC) cannot be explained by a previously proposed relay from AC based on response properties. By combining anatomical tracing and optogenetic/pharmacological manipulations, we discovered that EC received auditory input primarily from the medial septum (MS), rather than AC. A previously uncharacterized auditory pathway was then revealed: it branched from the cochlear nucleus, and via caudal pontine reticular nucleus, pontine central gray, and MS, reached EC. Neurons along this non-canonical auditory pathway responded selectively to high-intensity broadband noise, but not pure tones. Disruption of the pathway resulted in an impairment of specifically noise-cued fear conditioning. This reticular-limbic pathway may thus function in processing aversive acoustic signals., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Distinct subtypes of inhibitory interneuron are known to shape diverse rhythmic activities in the cortex, but how they interact to orchestrate specific band activity remains largely unknown. By recording optogenetically tagged interneurons of specific subtypes in the primary visual cortex of behaving mice, we show that spiking of somatostatin (SOM)- and parvalbumin (PV)-expressing interneurons preferentially correlates with cortical beta and gamma band oscillations, respectively. Suppression of SOM cell spiking reduces the spontaneous low-frequency band (<30-Hz) oscillations and selectively reduces visually induced enhancement of beta oscillation. In comparison, suppressing PV cell activity elevates the synchronization of spontaneous activity across a broad frequency range and further precludes visually induced changes in beta and gamma oscillations. Rhythmic activation of SOM and PV cells in the local circuit entrains resonant activity in the narrow 5- to 30-Hz band and the wide 20- to 80-Hz band, respectively. Together, these findings reveal differential and cooperative roles of SOM and PV inhibitory neurons in orchestrating specific cortical oscillations., (Copyright © 2017 Elsevier Inc. All rights reserved.)

To decipher neural circuits underlying brain functions, viral tracers are widely applied to map input and output connectivity of neuronal populations. Despite the successful application of retrograde transsynaptic viruses for identifying presynaptic neurons of transduced neurons, analogous anterograde transsynaptic tools for tagging postsynaptically targeted neurons remain under development. Here, we discovered that adeno-associated viruses (AAV1 and AAV9) exhibit anterograde transsynaptic spread properties. AAV1-Cre from transduced presynaptic neurons effectively and specifically drives Cre-dependent transgene expression in selected postsynaptic neuronal targets, thus allowing axonal tracing and functional manipulations of the latter input-defined neuronal population. Its application in superior colliculus (SC) reveals that SC neuron subpopulations receiving corticocollicular projections from auditory and visual cortex specifically drive flight and freezing, two different types of defense behavior, respectively. Together with an intersectional approach, AAV-mediated anterograde transsynaptic tagging can categorize neurons by their inputs and molecular identity, and allow forward screening of distinct functional neural pathways embedded in complex brain circuits., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Cross-modality interaction in sensory perception is advantageous for animals' survival. How cortical sensory processing is cross-modally modulated and what are the underlying neural circuits remain poorly understood. In mouse primary visual cortex (V1), we discovered that orientation selectivity of layer (L)2/3, but not L4, excitatory neurons was sharpened in the presence of sound or optogenetic activation of projections from primary auditory cortex (A1) to V1. The effect was manifested by decreased average visual responses yet increased responses at the preferred orientation. It was more pronounced at lower visual contrast and was diminished by suppressing L1 activity. L1 neurons were strongly innervated by A1-V1 axons and excited by sound, while visual responses of L2/L3 vasoactive intestinal peptide (VIP) neurons were suppressed by sound, both preferentially at the cell's preferred orientation. These results suggest that the cross-modality modulation is achieved primarily through L1 neuron- and L2/L3 VIP-cell-mediated inhibitory and disinhibitory circuits., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Innate defense behaviors (IDBs) evoked by threatening sensory stimuli are essential for animal survival. Although subcortical circuits are implicated in IDBs, it remains largely unclear whether sensory cortex modulates IDBs and what the underlying neural pathways are. Here, we show that optogenetic silencing of corticotectal projections from layer 5 (L5) of the mouse primary visual cortex (V1) to the superior colliculus (SC) significantly reduces an SC-dependent innate behavior (i.e., temporary suspension of locomotion upon a sudden flash of light as short as milliseconds). Surprisingly, optogenetic activation of SC-projecting neurons in V1 or their axon terminals in SC sufficiently elicits the behavior, in contrast to other major L5 corticofugal projections. Thus, via the same corticofugal projection, visual cortex not only modulates the light-induced arrest behavior, but also can directly drive the behavior. Our results suggest that sensory cortex may play a previously unrecognized role in the top-down initiation of sensory-motor behaviors., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Binaural integration in the central nucleus of inferior colliculus (ICC) plays a critical role in sound localization. However, its arithmetic nature and underlying synaptic mechanisms remain unclear. Here, we showed in mouse ICC neurons that the contralateral dominance is created by a "push-pull"-like mechanism, with contralaterally dominant excitation and more bilaterally balanced inhibition. Importantly, binaural spiking response is generated apparently from an ipsilaterally mediated scaling of contralateral response, leaving frequency tuning unchanged. This scaling effect is attributed to a divisive attenuation of contralaterally evoked synaptic excitation onto ICC neurons with their inhibition largely unaffected. Thus, a gain control mediates the linear transformation from monaural to binaural spike responses. The gain value is modulated by interaural level difference (ILD) primarily through scaling excitation to different levels. The ILD-dependent synaptic scaling and gain adjustment allow ICC neurons to dynamically encode interaural sound localization cues while maintaining an invariant representation of other independent sound attributes., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Orientation selectivity (OS) is an emergent property in the primary visual cortex (V1). How OS arises from synaptic circuits remains unsolved. Here, in vivo whole-cell recordings in the mouse V1 revealed that simple cells received broadly tuned excitation and even more broadly tuned inhibition. Excitation and inhibition shared a similar orientation preference and temporally overlapped substantially. Neuron modeling and dynamic-clamp recording further revealed that excitatory inputs alone would result in membrane potential responses with significantly attenuated selectivity, due to a saturating input-output function of the membrane filtering. Inhibition ameliorated the attenuation of excitatory selectivity by expanding the input dynamic range and caused additional sharpening of output responses beyond unselectively suppressing responses at all orientations. This "blur-sharpening" effect allows selectivity conveyed by excitatory inputs to be better expressed, which may be a general mechanism underlying the generation of feature-selective responses in the face of strong excitatory inputs that are weakly biased., (Copyright © 2011 Elsevier Inc. All rights reserved.)

A canonical feedforward circuit is proposed to underlie sensory cortical responses with balanced excitation and inhibition in layer 4 (L4). However, in another input layer, L6, sensory responses and the underlying synaptic circuits remain largely unclear. Here, cell-attached recordings in rat primary auditory cortex revealed that for the majority of L6 excitatory neurons, tonal stimuli did not drive spike responses, but suppressed spontaneous firings. Whole-cell recordings further revealed that the silencing resulted from tone-evoked strong inhibition arriving earlier than excitation. This pattern of inputs can be attributed to a parallel feedforward circuit with both excitatory and inhibitory inputs disynaptically relayed. In contrast, in the other neurons directly driven by thalamic input, stimuli evoked excitation preceding relatively weak inhibition, resulting in robust spike responses. Thus, the dichotomy of L6 response properties arises from two distinct patterns of excitatory-inhibitory interplay. The parallel circuit module generating preceding inhibition may provide a gating mechanism for conditional corticothalamic feedback., (Copyright 2010 Elsevier Inc. All rights reserved.)

Metaplasticity refers to an activity-dependent regulation of the plastic state of neurons. In this issue of Neuron, Dunfield and Haas demonstrate that in intact developing brain circuits, specific patterns of visual stimulation drive functional plasticity of individual neurons with variable outcomes, predisposed by time-averaged postsynaptic activity recent to visual training.

Cortical inhibition plays an important role in shaping neuronal processing. The underlying synaptic mechanisms remain controversial. Here, in vivo whole-cell recordings from neurons in the rat primary auditory cortex revealed that the frequency tuning curve of inhibitory input was broader than that of excitatory input. This results in relatively stronger inhibition in frequency domains flanking the preferred frequencies of the cell and a significant sharpening of the frequency tuning of membrane responses. The less selective inhibition can be attributed to a broader bandwidth and lower threshold of spike tonal receptive field of fast-spike inhibitory neurons than nearby excitatory neurons, although both types of neurons receive similar ranges of excitatory input and are organized into the same tonotopic map. Thus, the balance between excitation and inhibition is only approximate, and intracortical inhibition with high sensitivity and low selectivity can laterally sharpen the frequency tuning of neurons, ensuring their highly selective representation.

The neural circuitry that constrains visual acuity in the CNS has not been experimentally identified. We show here that zebrafish blumenkohl (blu) mutants are impaired in resolving rapid movements and fine spatial detail. The blu gene encodes a vesicular glutamate transporter expressed by retinal ganglion cells. Mutant retinotectal synapses release less glutamate, per vesicle and per terminal, and fatigue more quickly than wild-type in response to high-frequency stimulation. In addition, mutant axons arborize more extensively, thus increasing the number of synaptic terminals and effectively normalizing the combined input to postsynaptic cells in the tectum. This presumably homeostatic response results in larger receptive fields of tectal cells and a degradation of the retinotopic map. As predicted, mutants have a selective deficit in the capture of small prey objects, a behavior dependent on the tectum. Our studies successfully link the disruption of a synaptic protein to complex changes in neural circuitry and behavior.

Intensity-tuned neurons, characterized by their nonmonotonic response-level function, may play important roles in the encoding of sound intensity-related information. The synaptic mechanisms underlying intensity tuning remain unclear. Here, in vivo whole-cell recordings in rat auditory cortex revealed that intensity-tuned neurons, mostly clustered in a posterior zone, receive imbalanced tone-evoked excitatory and inhibitory synaptic inputs. Excitatory inputs exhibit nonmonotonic intensity tuning, whereas with tone intensity increments, the temporally delayed inhibitory inputs increase monotonically in strength. In addition, this delay reduces with the increase of intensity, resulting in an enhanced suppression of excitation at high intensities and a significant sharpening of intensity tuning. In contrast, non-intensity-tuned neurons exhibit covaried excitatory and inhibitory inputs, and the relative time interval between them is stable with intensity increments, resulting in monotonic response-level function. Thus, cortical intensity tuning is primarily determined by excitatory inputs and shaped by cortical inhibition through a dynamic control of excitatory and inhibitory timing.

The receptive field (RF) of single visual neurons undergoes progressive refinement during development. It remains largely unknown how the excitatory and inhibitory inputs on single developing neurons are refined in a coordinated manner to allow the formation of functionally correct circuits. Using whole-cell voltage-clamp recording from Xenopus tectal neurons, we found that RFs determined by excitatory and inhibitory inputs in more mature tectal neurons are spatially matched, with each spot stimulus evoking balanced synaptic excitation and inhibition. This emerges during development through a gradual reduction in the RF size and a transition from disparate to matched topography of excitatory and inhibitory inputs to the tectal neurons. Altering normal spiking activity of tectal neurons by either blocking or elevating GABA(A) receptor activity significantly impeded the developmental reduction and topographic matching of RFs. Thus, appropriate inhibitory activity is essential for the coordinated refinement of excitatory and inhibitory connections.

Input specificity of activity-induced synaptic modification was examined in the developing Xenopus retinotectal connections. Early in development, long-term potentiation (LTP) induced by theta burst stimulation (TBS) at one retinal input spreads to other unstimulated converging inputs on the same tectal neuron. As the animal develops, LTP induced by the same TBS becomes input specific, a change that correlates with the increased complexity of tectal dendrites and more restricted distribution of dendritic Ca(2+) evoked by each retinal input. In contrast, LTP induced by 1 Hz correlated pre- and postsynaptic spiking is input specific throughout the same developmental period. Thus, input specificity of LTP emerges with neural development and depends on the pattern of synaptic activity.