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Effective detection and avoidance from environmental threats are crucial for animals' survival. Integration of sensory cues associated with threats across different modalities can significantly enhance animals' detection and behavioral responses. However, the neural circuit-level mechanisms underlying the modulation of defensive behavior or fear response under simultaneous multimodal sensory inputs remain poorly understood. Here, we report in mice that bimodal looming stimuli combining coherent visual and auditory signals elicit more robust defensive/fear reactions than unimodal stimuli. These include intensified escape and prolonged hiding, suggesting a heightened defensive/fear state. These various responses depend on the activity of the superior colliculus (SC), while its downstream nucleus, the parabigeminal nucleus (PBG), predominantly influences the duration of hiding behavior. PBG temporally integrates visual and auditory signals and enhances the salience of threat signals by amplifying SC sensory responses through its feedback projection to the visual layer of the SC. Our results suggest an evolutionarily conserved pathway in defense circuits for multisensory integration and cross-modality enhancement., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 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.)

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.)

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.)

In many sensory systems, receptive fields (RFs) measured by spike responses undergo progressive refinement during development. It has been proposed that elimination of excitatory synaptic inputs underlies such functional refinement. However, despite many extracellular recording and anatomical studies, direct in vivo intracellular evidence has remained limited. In this study, by cell-attached recordings in the developing optic tectum of zebrafish, we found that during a short period after the initial formation of retinotectal synapses, spike visual RFs of tectal neurons underwent a two-stage developmental modulation: from an initial expansion to a later refinement. Whole-cell voltage-clamp recordings revealed that the underlying excitatory synaptic RF exhibited a similar developmental progression, with its spatial extent first increased and then reduced, and its spatial tuning profile gradually sharpened. The inhibitory RF was initially larger than the excitatory RF but became matched with the excitatory RF at later stages. Simulation with the integrate-and-fire neuron model suggested that the developmental changes of excitatory RFs primarily accounted for the initial enlargement and later refinement of spike RFs, whereas inhibitory inputs generally reduced the size of the spike RF without affecting its developmental progression. In addition, spike RF of individual retinal ganglion cells did not significantly change in size during the same period, and the spatial extent and tuning profile of the tectal excitatory RF barely changed after intratectal excitatory connections were silenced. Together, our results demonstrate that the functional refinement of tectal visual RFs results primarily from a selective elimination of feedforward retinotectal inputs.

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.

Persistent synaptic modifications are essential for experience-dependent refinement of developing circuits. However, in the developing Xenopus retinotectal system, activity-induced synaptic modifications were quickly reversed either by subsequent spontaneous activity in the tectum or by exposure to random visual inputs. This reversal depended on the burst spiking and activation of the N-methyl-D-aspartate subtype of glutamate receptors. Stabilization of synaptic modifications can be achieved by an appropriately spaced pattern of induction stimuli. These findings underscore the vulnerable nature of activity-induced synaptic modifications in vivo and suggest a temporal constraint on the pattern of visual inputs for effective induction of stable synaptic modifications.

During development of the visual system, the pattern of visual inputs may have an instructive role in refining developing neural circuits. How visual inputs of specific spatiotemporal patterns shape the circuit development remains largely unknown. We report here that, in the developing Xenopus retinotectal system, the receptive field of tectal neurons can be 'trained' to become direction-sensitive within minutes after repetitive exposure of the retina to moving bars in a particular direction. The induction of direction-sensitivity depends on the speed of the moving bar, can not be induced by random visual stimuli, and is accompanied by an asymmetric modification of the tectal neuron's receptive field. Furthermore, such training-induced changes require spiking of the tectal neuron and activation of a NMDA (N-methyl-D-aspartate) subtype of glutamate receptors during training, and are attributable to an activity-induced enhancement of glutamate-mediated inputs. Thus, developing neural circuits can be modified rapidly and specifically by visual inputs of defined spatiotemporal patterns, in a manner consistent with predictions based on spike-time-dependent synaptic modification.

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.

Early visual experience is essential in the refinement of developing neural connections. In vivo whole-cell recording from the tectum of Xenopus tadpoles showed that repetitive dimming-light stimulation applied to the contralateral eye resulted in persistent enhancement of glutamatergic inputs, but not GABAergic or glycinergic inputs, on tectal neurons. This enhancement can be attributed to potentiation of retinotectal synapses. It required spiking of postsynaptic tectal cells as well as activation of NMDA receptors, and effectively occluded long-term potentiation (LTP) of retinotectal synapses induced by direct electrical stimulation of retinal ganglion cells. Thus, LTP-like synaptic modification can be induced by natural visual inputs and may be part of the underlying mechanism for the activity-dependent refinement of developing connections.

In the developing frog visual system, topographic refinement of the retinotectal projection depends on electrical activity. In vivo whole-cell recording from developing Xenopus tectal neurons shows that convergent retinotectal synapses undergo activity-dependent cooperation and competition following correlated pre- and postsynaptic spiking within a narrow time window. Synaptic inputs activated repetitively within 20 ms before spiking of the tectal neuron become potentiated, whereas subthreshold inputs activated within 20 ms after spiking become depressed. Thus both the initial synaptic strength and the temporal order of activation are critical for heterosynaptic interactions among convergent synaptic inputs during activity-dependent refinement of developing neural networks.