Widespread presence of direction-reversing neurons in the mouse visual system

Direction selectivity, the preference of motion in one direction over the opposite, is a fundamental property of visual neurons across species. We find that a substantial proportion of direction selective neurons in the mouse visual system reverse their preferred direction of motion in response to drifting gratings at different spatiotemporal parameters. A spatiotemporally asymmetric filter model recapitulates our experimental observations

Widespread presence of direction-reversing neurons in the mouse visual system

Direction selectivity, the preference of motion in one direction over the opposite, is a fundamental property of visual neurons across species. We find that a substantial proportion of direction selective neurons in the mouse visual system reverse their preferred direction of motion in response to drifting gratings at different spatiotemporal parameters. A spatiotemporally asymmetric filter model recapitulates our experimental observations

Reconciling functional differences in populations of neurons recorded with two-photon imaging and electrophysiology

Extracellular electrophysiology and two-photon calcium imaging are widely used methods for measuring physiological activity with single cell resolution across large populations of neurons in the brain. While these two modalities have distinct advantages and disadvantages, neither provides complete, unbiased information about the underlying neural population. Here, we compare evoked responses in visual cortex recorded in awake mice under highly standardized conditions using either imaging or electrophysiology. Across all stimulus conditions tested, we observe a larger fraction of responsive neurons in electrophysiology and higher stimulus selectivity in calcium imaging. This work explores which data transformations are most useful for explaining these modality specific discrepancies. We show that the higher selectivity in imaging can be partially reconciled by applying a spikes-to-calcium forward model to the electrophysiology data. However, the forward model could not reconcile differences in responsiveness without sub selecting neurons based on event rate or level of signal contamination. This suggests that differences in responsiveness more likely reflect neuronal sampling bias or cluster merging artifacts during spike sorting of electrophysiological recordings, rather than flaws in event detection from fluorescence time series. This work establishes the dominant impacts of the two modalities9 respective biases on a set of functional metrics that are fundamental for characterizing sensory-evoked responses.R01 EB026908 - NIBIB NIH HHShttps://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC8285106&blobtype=pdfPublished versio

Cellular anatomy of the mouse primary motor cortex.

An essential step toward understanding brain function is to establish a structural framework with cellular resolution on which multi-scale datasets spanning molecules, cells, circuits and systems can be integrated and interpreted1. Here, as part of the collaborative Brain Initiative Cell Census Network (BICCN), we derive a comprehensive cell type-based anatomical description of one exemplar brain structure, the mouse primary motor cortex, upper limb area (MOp-ul). Using genetic and viral labelling, barcoded anatomy resolved by sequencing, single-neuron reconstruction, whole-brain imaging and cloud-based neuroinformatics tools, we delineated the MOp-ul in 3D and refined its sublaminar organization. We defined around two dozen projection neuron types in the MOp-ul and derived an input-output wiring diagram, which will facilitate future analyses of motor control circuitry across molecular, cellular and system levels. This work provides a roadmap towards a comprehensive cellular-resolution description of mammalian brain architecture

Excessive cocaine use results from decreased phasic dopamine signaling in the striatum

Drug addiction is a neuropsychiatric disorder marked by escalating drug use. Dopamine neurotransmission in the ventromedial striatum (VMS) mediates acute reinforcing effects of abused drugs, but with protracted use the dorsolateral striatum is thought to assume control over drug seeking. We measured striatal dopamine release during a cocaine self-administration regimen that produced escalation of drug taking in rats. Surprisingly, we found that phasic dopamine decreased in both regions as the rate of cocaine intake increased, with the decrement in dopamine in the VMS significantly correlated with the rate of escalation. Administration of the dopamine precursor L-DOPA at a dose that replenished dopamine signaling in the VMS reversed escalation, thereby demonstrating a causal relationship between diminished dopamine transmission and excessive drug use. Together these data provide mechanistic and therapeutic insight into the excessive drug intake that emerges following protracted use

Repeated stress exposure causes strain-dependent shifts in the behavioral economics of cocaine in rats

Cocaine-experienced Wistar and Wistar Kyoto (WKY) rats received four daily repeated forced swim stress sessions (R-FSS), each of which preceded 4-hour cocaine self-administration sessions. Twenty-four hours after the last swim stress, cocaine valuation was assessed during a single-session threshold procedure. Prior exposure to R-FSS significantly altered cocaine responding in Wistar, but not WKY, rats. Behavioral economic analysis of responding revealed that the Wistar rats that had received R-FSS exhibited an increase in the maximum price that they were willing to pay for cocaine (P-max). Pre-treatment with the long-lasting kappa opioid receptor (KOR) antagonist norbinaltorphimine prevented the stress-induced increase in P-max. Thus, R-FSS exposure had strain-dependent effects on cocaine responding during the threshold procedure, and the stress effects on cocaine valuation exhibited by Wistar, but not WKY, required intact KOR signalin

Chronic Dysfunction of Astrocytic Inwardly Rectifying K+ Channels Specific to the Neocortical Epileptic Focus After Fluid Percussion Injury in the Rat

Astrocytic inwardly rectifying K+ currents (IKIR) have an important role in extracellular K+ homeostasis, which influences neuronal excitability, and serum extravasation has been linked to impaired KIR-mediated K+ buffering and chronic hyperexcitability. Head injury induces acute impairment in astroglial membrane IKIR and impaired K+ buffering in the rat hippocampus, but chronic spontaneous seizures appear in the perilesional neocortex—not the hippocampus—in the early weeks to months after injury. Thus we examined astrocytic KIR channel pathophysiology in both neocortex and hippocampus after rostral parasaggital fluid percussion injury (rpFPI). rpFPI induced greater acute serum extravasation and metabolic impairment in the perilesional neocortex than in the underlying hippocampus, and in situ whole cell recordings showed a greater acute loss of astrocytic IKIR in neocortex than hippocampus. IKIR loss persisted through 1 mo after injury only in the neocortical epileptic focus, but fully recovered in the hippocampus that did not generate chronic seizures. Neocortical cell-attached recordings showed no loss or an increase of IKIR in astrocytic somata. Confocal imaging showed depletion of KIR4.1 immunoreactivity especially in processes—not somata—of neocortical astrocytes, whereas hippocampal astrocytes appeared normal. In naïve animals, intracortical infusion of serum, devoid of coagulation-mediating thrombin activity, reproduces the effects of rpFPI both in vivo and at the cellular level. In vivo serum infusion induces partial seizures similar to those induced by rpFPI, whereas bath-applied serum, but not dialyzed albumin, rapidly silenced astrocytic KIR membrane currents in whole cell and cell-attached patch-clamp recordings in situ. Thus both acute impairment in astrocytic IKIR and chronic spontaneous seizures typical of rpFPI are reproduced by serum extravasation, whereas the chronic impairment in astroglial IKIR is specific to the neocortex that develops the epileptic focus

Next-generation brain observatories

We propose centralized brain observatories for large-scale recordings of neural activity in mice and non-human primates coupled with cloud-based data analysis and sharing. Such observatories will advance reproducible systems neuroscience and democratize access to the most advanced tools and data.UPMWMATHI