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.

Parkinson’s disease (PD) is characterized by progressive dopamine (DA) neuron loss in the substantia nigra pars compacta (SNc). In contrast, DA neurons in the ventral tegmental area (VTA) are relatively protected from neurodegeneration, but the underlying mechanisms for this resilience remain poorly understood. Recent work suggests that expression of the vesicular glutamate transporter 2 (VGLUT2) selectively impacts midbrain DA neuron vulnerability. We investigated whether altered DA neuron VGLUT2 expression determines neuronal resilience in rats exposed to rotenone, a mitochondrial complex I inhibitor and toxicant model of PD. We discovered that VTA/SNc DA neurons that expressed VGLUT2 are more resilient to rotenone-induced DA neurodegeneration. Surprisingly, the density of neurons with detectable VGLUT2 expression in the VTA and SNc increases in response to rotenone. Furthermore, dopaminergic terminals within the nucleus accumbens, where the majority of VGLUT2-expressing DA neurons project, exhibit great...

Double cones are the most common photoreceptor cell type in most avian retinas, but their precise functions remain a mystery. Among their suggested functions are luminance detection, polarized light detection, and light-dependent, radical-pair-based magnetoreception. To better understand the function of double cones, it will be crucial to know how they are connected to the neural network in the avian retina. Here we use serial sectioning, multi-beam scanning electron microscopy (ssmSEM) to investigate double cone anatomy and connectivity with a particular focus on their contacts to other photoreceptor and bipolar cells in the chicken retina. We found that double cones are highly connected with neighbouring double cones and with other photoreceptor cells through telodendria-to-terminal and telodendria-to-telodendria contacts. We also identified 15 bipolar cell types based on their axonal stratifications, photoreceptor contact pattern, soma position, and dendritic and axonal field mosaics. Thirteen of these ...

Human corticospinal transmission is commonly studied using brain stimulation. However, this approach is biased to activity in the fastest conducting axons. It is unclear whether conclusions obtained in this context are representative of volitional activity in mild-to-moderate contractions. An alternative to overcome this limitation may be to study the corticospinal transmission of endogenously generated brain activity. Here we investigate in humans (N=19; of either sex), the transmission speeds of cortical beta rhythms (∼20Hz) traveling to arm (first dorsal interosseous) and leg (tibialis anterior) muscles during tonic mild contractions. For this purpose, we propose two improvements for the estimation of cortico-muscular beta transmission delays. First, we show that the cumulant density (cross-covariance) is more accurate than the commonly-used directed coherence to estimate transmission delays in bidirectional systems transmitting band-limited signals. Second, we show that when spiking motor unit activity...

Fragile X syndrome (FXS) is a neurodevelopmental disorder (NDD) characterized by intellectual disability, autism spectrum disorders (ASDs), and anxiety disorders. The disruption in the function of the FMR1 gene results in a range of alterations in cellular and synaptic function. Previous studies have identified dynamic alterations in inhibitory neurotransmission in early postnatal development in the amygdala of the mouse model of FXS. However, little is known about how these changes alter microcircuit development and plasticity in the lateral amygdala (LA). Using whole-cell patch clamp electrophysiology, we demonstrate that principal neurons (PNs) in the LA exhibit hyperexcitability with a concomitant increase in the synaptic strength of excitatory synapses in the BLA. Further, reduced feed-forward inhibition appears to enhance synaptic plasticity in the FXS amygdala. These results demonstrate that plasticity is enhanced in the amygdala of the juvenile Fmr1 knock-out (KO) mouse and that E/I imbalance may u...