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.

To decipher neural circuits underlying brain functions, viral tracers are widely applied to map input and output connectivity of specific 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 report that adeno-associated virus (AAV1 and AAV9) exhibit anterograde transsynaptic spread properties. AAV1-Cre from transduced presynaptic neurons effectively and specifically drove Cre-dependent transgene expression in selected postsynaptic neuronal targets, and thus allowed the tracing and functional manipulation of axonal projections from the latter input-defined neuronal population. Application of this tool in superior colliculus (SC) revealed that SC neuron subpopulations receiving corticocollicular projections from auditory and visual cortex specifically drove flight and freezing, two different types of defense behavior, respectively. Such anterograde transsynaptic tagging is thus useful for forward screening of distinct functional neural pathways embedded in complex brain circuits.

Cortical sensory processing is modulated by behavioral and cognitive states. How the modulation is achieved through impacting synaptic circuits remains largely unknown. In awake mouse auditory cortex, we reported that sensory-evoked spike responses of layer 2/3 (L2/3) excitatory cells were scaled down with preserved sensory tuning when animals transitioned from quiescence to active behaviors, while L4 and thalamic responses were unchanged. Whole-cell voltage-clamp recordings further revealed that tone-evoked synaptic excitation and inhibition exhibited a robust functional balance. Changes of behavioral state caused scaling down of excitation and inhibition at an approximately equal level in L2/3 cells, but no synaptic changes in L4 cells. This laminar-specific gain control could be attributed to an enhancement of L1–mediated inhibitory tone, with L2/3 parvalbumin inhibitory neurons suppressed as well. Thus, L2/3 circuits can adjust the salience of output in accordance with momentary behavioral demands while maintaining the sensitivity and quality of sensory processing.

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.

Summary 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 L2/3 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 L2/3 VIP-cell mediated inhibitory and disinhibitory circuits.