Inhibitory interneurons play a crucial role in proper development and function of the mammalian cerebral cortex. Of the different inhibitory subclasses, dendritic-targeting, somatostatin-containing (SOM) interneurons may be the most diverse. Earlier studies used GFP-expressing and recombinase-expressing mouse lines to characterize genetically defined subtypes of SOM interneurons by morphologic, electrophysiological, and neurochemical properties. More recently, large-scale studies classified SOM interneurons into 13 morpho-electric transcriptomic (MET) types. It remains unclear, however, how these various classification schemes relate to each other, and experimental access to MET types has been limited by the scarcity of specific mouse driver lines. To address these issues, we crossed Flp and Cre driver lines with a dual-color intersectional reporter, allowing experimental access to several combinatorially defined SOM subsets. Brains from adult mice of both sexes were retrogradely dye labeled from the pial ...

AMPA receptors (AMPARs) are the major mediators of fast excitatory neurotransmission in the retina as in other parts of the brain. In most neurons, the synaptic targeting, pharmacology, and function of AMPARs are influenced by auxiliary subunits including the transmembrane AMPA receptor regulatory proteins (TARPs). However, it is unclear which TARP subunits are present at retinal synapses and how they influence receptor localization and function. Here, we show that TARPɣ2 (stargazin) is associated with AMPARs in the synaptic layers of the mouse, rabbit, macaque, and human retina. In most species, TARPɣ2 expression was high where starburst amacrine cells (SACs) ramify and transcriptomic analyses suggest correspondingly high gene expression in mouse and human SACs. Synaptic expression of GluA2, GluA3, and GluA4 was significantly reduced in a mouse mutant lacking TARPɣ2 expression (stargazer mouse; stg ), whereas GluA1 levels were unaffected. AMPAR-mediated light-evoked EPSCs in ON-SACs from stg mice were ∼30...

Estradiol, a female sex hormone and the predominant form of estrogen, has diverse effects throughout the brain including in learning and memory. Estradiol modulates several types of learning that depend on the dorsomedial striatum (DMS), a subregion of the basal ganglia involved in goal-directed learning, cued action-selection, and motor skills. A cellular basis of learning is synaptic plasticity, and the presence of extranuclear estradiol receptors ERα, ERβ, and G-protein-coupled estrogen receptor (GPER) throughout the DMS suggests that estradiol may influence rapid cellular actions including those involved in plasticity. To test whether estradiol affects synaptic plasticity in the DMS, corticostriatal long-term potentiation (LTP) was induced using theta-burst stimulation (TBS) in ex vivo brain slices from intact male and female C57BL/6 mice. Extracellular field recordings showed that female mice in the diestrous stage of the estrous cycle exhibited LTP similar to male mice, while female mice in estrus di...

In implicit sensorimotor adaptation, a mismatch between the predicted and actual sensory feedback results in a sensory prediction error (SPE). Sensory predictions have long been thought to be linked to descending motor commands, implying a necessary contribution of movement execution to adaptation. However, recent work has shown that mere motor imagery (MI) also engages predictive mechanisms, opening up the possibility that MI might be sufficient to drive implicit adaptation. In a within-subject design in humans ( n  = 30), implicit adaptation was assessed in a center-out reaching task, following a single exposure to a visuomotor rotation. It was hypothesized that performing MI of a reaching movement while being provided with an animation of rotated visual feedback (MI condition) would lead to postrotation biases (PRBs) similar to those observed when the movement is executed (Execution condition). Results revealed that both the MI and Execution conditions led to significant directional biases following rot...

When listening to speech, the low-frequency cortical response below 10 Hz can track the speech envelope. Previous studies have demonstrated that the phase lag between speech envelope and cortical response can reflect the mechanism by which the envelope-tracking response is generated. Here, we analyze whether the mechanism to generate the envelope-tracking response is modulated by the level of consciousness, by studying how the stimulus-response phase lag is modulated by the disorder of consciousness (DoC). It is observed that DoC patients in general show less reliable neural tracking of speech. Nevertheless, the stimulus-response phase lag changes linearly with frequency between 3.5 and 8 Hz, for DoC patients who show reliable cortical tracking to speech, regardless of the consciousness state. The mean phase lag is also consistent across these DoC patients. These results suggest that the envelope-tracking response to speech can be generated by an automatic process that is barely modulated by the consciousn...

How rapidly can the brain transform vision into action? Work in humans has established that the transformation for visually-guided reaching can be remarkably rapid, with the first phase of upper limb muscle recruitment, the express visuomotor response, beginning within less than 100 ms of visual target presentation. Such short-latency responses limit the opportunities for extensive cortical processing, leading to the hypothesis that they are generated via the subcortical tecto-reticulo-spinal pathway. Here, we examine whether nonhuman primates (NHPs) exhibit express visuomotor responses. Two male macaques made visually-guided reaches in a behavioral paradigm known to elicit express visuomotor responses in humans, while we acquired intramuscular recordings from the deltoid muscle. Across several variants of this paradigm, express visuomotor responses began within 65 ms (range: 48–91 ms) of target presentation. Although the timing of the express visuomotor response did not co-vary with reaction time, larger ...

Life-supporting rhythmic motor functions like heart-beating in invertebrates and breathing in vertebrates require an indefatigable generation of a robust rhythm by specialized oscillatory circuits, central pattern generators (CPGs). These CPGs should be sufficiently flexible to adjust to environmental changes and behavioral goals. Continuous self-sustained operation of bursting neurons requires intracellular Na+ concentration to remain in a functional range and to have checks and balances of the Na+ fluxes met on a cycle-to-cycle basis during bursting. We hypothesize that at a high excitability state, the interaction of the Na+/K+ pump current, Ipump, and persistent Na+ current, INaP, produces a mechanism supporting functional bursting. INaP is a low voltage-activated inward current that initiates and supports the bursting phase. This current does not inactivate and is a significant source of Na+ influx. Ipump is an outward current activated by [Na+]i and is the major source of Na+ efflux. Both currents ar...

Expanding knowledge about the cellular composition of subcortical brain regions demonstrates large heterogeneity and differences from the cortical architecture. Previously we described three subtypes of somatostatin-expressing (Sst) neurons in the mouse ventral tegmental area (VTA) and showed their local inhibitory action on the neighboring dopaminergic neurons ([Nagaeva et al., 2020][1]). Here, we report that Sst+ neurons especially from the anterolateral part of the mouse VTA also project far outside the VTA and innervate forebrain regions that are mainly involved in the regulation of emotional behavior, including the ventral pallidum, lateral hypothalamus, the medial part of the central amygdala, anterolateral division of the bed nucleus of stria terminalis, and paraventricular thalamic nucleus. Deletion of these VTASst neurons in mice affected several behaviors, such as home cage activity, sensitization of locomotor activity to morphine, fear conditioning responses, and reactions to the inescapable str...

A single 1-h session (or 7 d of daily 1-h sessions) of noninvasive visual stimulation with LED light flickering at 40 Hz, but not at 20 or 80 Hz, was reported to increase microglial size and decrease amyloid β (Aβ) load in the 5xFAD mouse model of Alzheimer’s disease. To achieve better therapeutic benefits, we explored the effects of daily 1-h sessions of visual stimulation with continuous light or LED light flickering at 24, 40, or 80 Hz for a period of five weeks in 5xFAD mice. As expected, 33-week-old 5xFAD mice but not control wild-type mice of the same age exhibited an abundance of swollen microglia and Aβ plaques in the visual cortex and hippocampus. Unexpectedly, however, compared with similar session of stimulation with continuous light or a light flickering at 24 or 80 Hz, daily sessions of stimulation with LED light flickering at 40 Hz for five weeks failed to further increase the microglial size and could not noticeably decrease the Aβ load in the visual cortex and hippocampus of the 5xFAD mice....

Synaptic plasticity is a fundamental feature of the CNS that controls the magnitude of signal transmission between communicating cells. Many electrical synapses exhibit substantial plasticity that modulates the degree of coupling within groups of neurons, alters the fidelity of signal transmission, or even reconfigures functional circuits. In several known examples, such plasticity depends on calcium and is associated with neuronal activity. Calcium-driven signaling is known to promote potentiation of electrical synapses in fish Mauthner cells, mammalian retinal AII amacrine cells, and inferior olive neurons, and to promote depression in thalamic reticular neurons. To measure local calcium dynamics in situ , we developed a transgenic mouse expressing a GCaMP calcium biosensor fused to Connexin 36 (Cx36) at electrical synapses. We examined the sources of calcium for activity-dependent plasticity in retina slices using confocal or Super-Resolution Radial Fluctuations imaging. More than half of Cx36-GCaMP gap...