Adult visual deprivation engages associative, presynaptic plasticity of thalamic input to cortex.

Associative plasticity at thalamocortical synapses is thought to be constrained by age in the mammalian cortex. However, here we show for the first time that prolonged visual deprivation induces robust and reversible plasticity at synapses between first order visual thalamus and cortical layer 4 pyramidal neurons. The plasticity is associative and expressed by changes in presynaptic function, thereby amplifying and relaying the change in efferent drive to the visual cortex.

Transcranial Low-Intensity Focused Ultrasound Stimulation of the Visual Thalamus Produces Long-Term Depression of Thalamocortical Synapses in the Adult Visual Cortex.

Transcranial focused ultrasound stimulation (tFUS) is a noninvasive neuromodulation technique, which can penetrate deeper and modulate neural activity with a greater spatial resolution (on the order of millimeters) than currently available noninvasive brain stimulation methods, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). While there are several studies demonstrating the ability of tFUS to modulate neuronal activity, it is unclear whether it can be used for producing long-term plasticity as needed to modify circuit function, especially in adult brain circuits with limited plasticity such as the thalamocortical synapses. Here we demonstrate that transcranial low-intensity focused ultrasound (LIFU) stimulation of the visual thalamus (dorsal lateral geniculate nucleus, dLGN), a deep brain structure, leads to NMDA receptor (NMDAR)-dependent long-term depression of its synaptic transmission onto layer 4 neurons in the primary visual cortex (V1) of adult mice of both sexes.

Norepinephrine potentiates and serotonin depresses visual cortical responses by transforming eligibility traces.

Reinforcement allows organisms to learn which stimuli predict subsequent biological relevance. Hebbian mechanisms of synaptic plasticity are insufficient to account for reinforced learning because neuromodulators signaling biological relevance are delayed with respect to the neural activity associated with the stimulus. A theoretical solution is the concept of eligibility traces (eTraces), silent synaptic processes elicited by activity which upon arrival of a neuromodulator are converted into a lasting change in synaptic strength.

Sensory- and Motor-Related Responses of Layer 1 Neurons in the Mouse Visual Cortex.

Cortical layer 1 (L1) contains a sparse and molecularly distinct population of inhibitory interneurons. Their location makes them ideally suited for affecting computations involving long-range corticocortical and subcortical inputs, yet their response properties remain largely unexplored. Here we attempt to characterize some of the functional properties of these neurons in the primary visual cortex of awake mice.

Disruption of NMDAR Function Prevents Normal Experience-Dependent Homeostatic Synaptic Plasticity in Mouse Primary Visual Cortex.

Homeostatic regulation of synaptic strength allows for maintenance of neural activity within a dynamic range for proper circuit function. There are largely two distinct modes of synaptic plasticity that allow for homeostatic adaptation of cortical circuits: synaptic scaling and sliding threshold (BCM theory). Previous findings suggest that the induction of synaptic scaling is not prevented by blocking NMDARs, whereas the sliding threshold model posits that the synaptic modification threshold of LTP and LTD readjusts with activity and thus the outcome of synaptic plasticity is NMDAR dependent.

A genetically encoded fluorescent acetylcholine indicator for in vitro and in vivo studies.

The neurotransmitter acetylcholine (ACh) regulates a diverse array of physiological processes throughout the body. Despite its importance, cholinergic transmission in the majority of tissues and organs remains poorly understood owing primarily to the limitations of available ACh-monitoring techniques. We developed a family of ACh sensors (GACh) based on G-protein-coupled receptors that has the sensitivity, specificity, signal-to-noise ratio, kinetics and photostability suitable for monitoring ACh signals in vitro and in vivo.

Inhibitory gain modulation of defense behaviors by zona incerta.

Zona incerta (ZI) is a functionally mysterious subthalamic nucleus containing mostly inhibitory neurons. Here, we discover that GABAergic neurons in the rostral sector of ZI (ZIr) directly innervate excitatory but not inhibitory neurons in the dorsolateral and ventrolateral compartments of periaqueductal gray (PAG), which can drive flight and freezing behaviors respectively. Optogenetic activation of ZIr neurons or their projections to PAG reduces both sound-induced innate flight response and conditioned freezing response, while optogenetic suppression of these neurons enhances these defensive behaviors, likely through a mechanism of gain modulation.

AAV-Mediated Anterograde Transsynaptic Tagging: Mapping Corticocollicular Input-Defined Neural Pathways for Defense Behaviors.

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.

Cross-Modality Sharpening of Visual Cortical Processing through Layer-1-Mediated Inhibition and Disinhibition.

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.

Functional response properties of VIP-expressing inhibitory neurons in mouse visual and auditory cortex.

Despite accounting for about 20% of all the layer 2/3 inhibitory interneurons, the vasoactive intestinal polypeptide (VIP) expressing neurons remain the least thoroughly studied of the major inhibitory subtypes. In recent studies, VIP neurons have been shown to be activated by a variety of cortico-cortical and neuromodulatory inputs, but their basic sensory response properties remain poorly characterized. We set out to explore the functional properties of layer 2/3 VIP neurons in the primary visual (V1) and primary auditory cortex (A1), using two-photon imaging guided patch recordings.

Thalamocortical Innervation Pattern in Mouse Auditory and Visual Cortex: Laminar and Cell-Type Specificity.

Despite many previous studies, the functional innervation pattern of thalamic axons and their target specificity remains to be investigated thoroughly. Here, in primary auditory cortical slices, we examined thalamic innervation patterns for excitatory and different types of inhibitory neurons across laminae, by optogenetically stimulating axons from the medial geniculate body. We found that excitatory cells and parvalbumin (PV)-expressing inhibitory neurons across layer 2/3 (L2/3) to L6 are directly innervated by thalamic projections, with the strongest innervation occurring in L4.

Interaural level difference-dependent gain control and synaptic scaling underlying binaural computation.

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.

Generation of spike latency tuning by thalamocortical circuits in auditory cortex.

In many sensory systems, the latency of spike responses of individual neurons is found to be tuned for stimulus features and proposed to be used as a coding strategy. Whether the spike latency tuning is simply relayed along sensory ascending pathways or generated by local circuits remains unclear. Here, in vivo whole-cell recordings from rat auditory cortical neurons in layer 4 revealed that the onset latency of their aggregate thalamic input exhibited nearly flat tuning for sound frequency, whereas their spike latency tuning was much sharper with a broadly expanded dynamic range.