Cholinergic modulation of cortex powerfully influences information processing and brain states, causing robust desynchronization of local field potentials and strong decorrelation of responses between neurons. Here we show that intracortical cholinergic inputs to mouse visual cortex specifically and differentially drive a defined cortical microcircuit: they facilitate somatostatin-expressing (SOM) inhibitory neurons that in turn inhibit parvalbumin-expressing inhibitory neurons and pyramidal neurons. Selective optogenetic inhibition of SOM responses blocks desynchronization and decorrelation, demonstrating that direct cholinergic activation of SOM neurons is necessary for this phenomenon. Optogenetic inhibition of vasoactive intestinal peptide-expressing neurons does not block desynchronization, despite these neurons being activated at high levels of cholinergic drive. Direct optogenetic SOM activation, independent of cholinergic modulation, is sufficient to induce desynchronization. Together, these findings demonstrate a mechanistic basis for temporal structure in cortical populations, and the crucial role of neuromodulatory drive to specific inhibitory-excitatory circuits in actively shaping the dynamics of neuronal activity.
Although cholinergic innervation of the cortex by the nucleus basalis (NB) is known to modulate cortical neuronal responses and instruct cortical plasticity, little is known about the underlying cellular mechanisms. Using cell-attached recordings in vivo, we demonstrate that electrical stimulation of the NB, paired with visual stimulation, can induce significant potentiation of visual responses in excitatory neurons of the primary visual cortex in mice. We further show with in vivo two-photon calcium imaging, ex vivo calcium imaging, and whole-cell recordings that this pairing-induced potentiation is mediated by direct cholinergic activation of primary visual cortex astrocytes via muscarinic AChRs. The potentiation is absent in conditional inositol 1,4,5 trisphosphate receptor type 2 KO mice, which lack astrocyte calcium activation, and is stimulus-specific, because pairing NB stimulation with a specific visual orientation reveals a highly selective potentiation of responses to the paired orientation compared with unpaired orientations. Collectively, these findings reveal a unique and surprising role for astrocytes in NB-induced stimulusspecific plasticity in the cerebral cortex.acetylcholine | response potentiation | glial calcium | basal forebrain | astrocyte-neuron interactions S ensory experience associated with nucleus basalis (NB)-driven, cholinergic activation of the cortex (1) has been shown to induce cortical plasticity at both single-cell and cortical map levels (2-6). To understand how cortical responses and representations can be altered by experience during cholinergic modulation, it is critical to identify the circuit elements involved and define how their interactions can contribute to the restructuring of cortical network dynamics.Previous studies have shown that multiple cortical cell types, including neurons (7-9) and astrocytes (10-12), can be responsive to ACh. Among these cell types, astrocytes are a promising candidate for contributing to NB-mediated cortical plasticity. Ex vivo studies have implicated hippocampal astrocytes in synaptic potentiation [(13-15) compare with (16)], demonstrating that they can potentially provide a powerful means of altering the state of neuronal networks to induce plasticity. More recently, studies using combined somatosensory and cholinergic stimulation have revealed that NB-induced astrocytic activation can induce potentiation of local field potentials recorded in somatosensory cortex (17,18). These findings open up several key questions. Does the NB-mediated potentiation manifest at the level of single neurons and astrocytes? If so, does the potentiation influence specific features of single neuronal responses and representations? In particular, is the potentiation a nonspecific increase in responses independent of sensory stimulus features, or does it selectively facilitate responses to stimuli that have been paired with NB stimulation?The primary visual cortex (V1) provides an excellent model system to address these issues. Modulation by ACh in general an...
Hyper-reactivity to sensory input is a common and debilitating symptom in individuals with autism spectrum disorders (ASD), but the neural basis underlying sensory abnormality is not completely understood. Here we examined the neural representations of sensory perception in the neocortex of a Shank3B −/− mouse model of ASD. Male and female Shank3B −/− mice were more sensitive to relatively weak tactile stimulation in a vibrissa motion detection task. In vivo population calcium imaging in vibrissa primary somatosensory cortex (vS1) revealed increased spontaneous and stimulus-evoked firing in pyramidal neurons but reduced activity in interneurons. Preferential deletion of Shank3 in vS1 inhibitory interneurons led to pyramidal neuron hyperactivity and increased stimulus sensitivity in the vibrissa motion detection task. These findings provide evidence that cortical GABAergic interneuron dysfunction plays a key role in sensory hyper-reactivity in a Shank3 mouse model of ASD and identify a potential cellular target for exploring therapeutic interventions.
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