Astrocytes exist throughout the CNS and are proposed to affect neural circuits and behaviour through intracellular Ca2+ signaling. Studying the function(s) of astrocyte Ca2+ signaling has proven difficult because of the paucity of tools to achieve selective attenuation. Based on recent studies, we generated and used male and female knock-in mice for Cre-dependent expression of mCherry-tagged hPMCA2w/b in order to attenuate astrocyte Ca2+ signaling in genetically defined cells in vivo (CalExflox mice for Calcium Extrusion). We characterized CalExflox mice following local AAV-Cre microinjections into the striatum and found reduced astrocyte Ca2+ signaling (∼90%) accompanied with repetitive self-grooming behaviour. We also crossed CalExflox mice to astrocyte specific Aldh1l1 -Cre/ERT2 mice in order to achieve inducible global CNS-wide Ca2+ signaling attenuation. Within six days of induction in the bigenic mice, we observed significantly altered ambulation in the open field, disrupted motor coordination and ga...

Many older listeners have difficulty understanding speech in noise, when cues to speech-sound identity are less redundant. The amplitude envelope of speech fluctuates dramatically over time, and features such as the rate of amplitude change at onsets (attack) and offsets (decay) signal critical information about the identity of speech sounds. Aging is also thought to be accompanied by increases in cortical excitability, which may differentially alter sensitivity to envelope dynamics. Here, we recorded electroencephalography in younger and older human adults (of both sexes) to investigate how aging affects neural synchronization to 4-Hz amplitude-modulated noises with different envelope shapes ( ramped : slow attack & sharp decay; damped : sharp attack & slow decay). We observed that subcortical responses did not differ between age groups, whereas older compared to younger adults exhibited larger cortical responses to sound onsets, consistent with an increase in auditory cortical excitability. Neural activi...

Humans have large social networks, with hundreds of interacting individuals. How does the brain represent the complex connectivity structure of these networks? Here we used social media (Facebook) data to objectively map participants’ real-life social networks. We then used representational similarity analysis (RSA) of fMRI activity patterns to investigate the neural coding of these social networks as participants reflected on each individual. We found coding of social network distances in the default-mode network (medial prefrontal, medial parietal and lateral parietal cortices). When using partial correlation RSA to control for other factors that can be correlated to social distance (personal affiliation, personality traits and visual appearance, as subjectively rated by the participants), we found that social network distance information was uniquely coded in the retrosplenial complex, a region involved in spatial processing. In contrast, information on individuals’ personal affiliation to the participa...

Developmental, cellular, and subcellular variations in the direction of neuronal Cl- currents elicited by GABAA receptor activation have been frequently reported. We found a corresponding variance in the reversal potential (EGABA) for synapses originating from individual interneurons onto a single pyramidal cell. These findings suggest a corresponding variance in the cytoplasmic concentration of Cl- ([Cl-i]) in individual dendrites. We determined [Cl-]i in the murine hippocampus and cerebral cortex of both sexes by: 1) two-photon imaging of the Cl- sensitive, ratiometric fluorescent protein SuperClomeleon (sCLM); 2) Fluorescence Lifetime IMaging (FLIM) of the Cl- sensitive fluorophore MEQ; and 3) electrophysiological measurements of EGABA by pressure application of GABA and RuBi-GABA uncaging. Fluorometric and electrophysiological estimates of local [Cl-]i were highly correlated. [Cl-]i microdomains persisted after pharmacological inhibition of cation-chloride cotransporters (CCCs), but were progressively ...

Neuropeptides are implicated in control of lateralized processes in the brain. A unilateral brain injury (UBI) causes the contra- and ipsilesional side-specific postural and sensorimotor deficits. To examine whether opioid neuropeptides mediate UBI induced asymmetric processes we compared effects of opioid antagonists on the contra- and ipsilesional hindlimb responses to the left- and right-sided injury in rats. UBI induced hindlimb postural asymmetry (HL-PA) with the contralesional hindlimb flexion, and activated contralesional withdrawal reflex of extensor digitorum longus (EDL) evoked by electrical stimulation and recorded with EMG technique. No effects on the interossei (Int) and peroneaus longus (PL) were evident. The general opioid antagonist naloxone blocked postural effects, did not change EDL asymmetry while uncovered cryptic asymmetry in the PL and Int reflexes induced by UBI. Thus the spinal opioid system may either mediate or counteract the injury effects. Strikingly, effects of selective opioi...

Environmental enrichment is beneficial to sensory functions. Thus, elucidating the neural mechanism underlying improvement of sensory stimulus discrimination is important for developing therapeutic strategies. We aim to advance the understanding of such neural mechanism. We found that tactile enrichment improved tactile stimulus feature discrimination. The neural correlate of such improvement was revealed by analyzing single-cell information coding in both the primary somatosensory cortex and the premotor cortex of awake behaving animals. Our results show that environmental enrichment enhances the decision-information coding capacity of cells that are tuned to adjacent whiskers, and of premotor cortical cells. Significance statement This study advances the understanding of the neural mechanisms underlying the improvement of tactile discrimination induced by tactile environmental enrichment. We demonstrate that enrichment improves the information-coding capacity of adjacent-whisker tuned cells in the bar...

Perception is an active process, requiring the integration of both proprioceptive and exteroceptive information. In the rat’s vibrissal system, a classical model for active sensing, the relative contribution of the two information streams was previously studied at the peripheral, thalamic and cortical levels. Contributions of brainstem neurons were only indirectly inferred for some trigeminal nuclei according to their thalamic projections. The current work addressed this knowledge gap by performing the first comparative study of the encoding of proprioceptive whisking and exteroceptive touch signals in the oralis (SpVo), interpolaris (SpVi) and paratrigeminal (Pa5) brainstem nuclei. We used artificial whisking in anesthetized male rats, which allows a systematic analysis of the relative contribution of the proprioceptive and exteroceptive information streams along the ascending pathways in the absence of motor or cognitive top-down modulations. We found that (i) neurons in the rostral and caudal parts of t...

Tau aggregation within neurons is a critical feature of Alzheimer’s disease (AD) and related tauopathies. It is believed that soluble pathologic tau species seed the formation of tau aggregates in a prion-like manner and propagate through connected neurons during the progression of disease. Both soluble and aggregated forms of tau are thought to have neurotoxic properties. In addition, different strains of misfolded tau may cause differential neurotoxicity. In this work, we present an accelerated human neuronal model of tau-induced neurotoxicity that incorporates both soluble tau species and tau aggregation. Using patient-derived induced pluripotent stem cell (iPSC) neurons expressing a tau aggregation biosensor, we develop a cell culture system that allows continuous assessment of both induced tau aggregation and neuronal viability at single-cell resolution for periods of >1 week. We show that exogenous tau “seed” uptake, as measured by tau repeat domain (TauRD) reporter aggregation, increases the risk fo...

The brain functions through coordinated activity among distributed regions. Wide-field calcium imaging, combined with improved genetically-encoded calcium indicators, allows sufficient signal-to-noise ratio and spatiotemporal resolution to afford a unique opportunity to capture cortex-wide dynamics on a moment-by-moment basis in behaving animals. Recent applications of this approach have been uncovering cortical dynamics at unprecedented scales during various cognitive processes, ranging from relatively simple sensorimotor integration to more complex decision-making tasks. In this review, we will highlight recent scientific advances enabled by wide-field calcium imaging in behaving mice. We then summarize several technical considerations and future opportunities for wide-field imaging to uncover large-scale circuit dynamics.