Spreading depolarizations (SDs) of gray matter occur in the brain in different pathologic conditions, and cause varying degrees of tissue damage depending on the extent of metabolic burden on the tissue. As might be expected for such large depolarizations, neurons exhibit bursts of action potentials (APs) as the wave propagates. However, the specific role of APs in SD propagation is unclear. This is potentially consequential, since sodium channel modulation has not been considered as a therapeutic target for SD-associated disorders, because of ambiguous experimental evidence. Using whole-cell electrophysiology and single-photon imaging in acute cortical slices from male C57Bl6 mice, we tested the effects of AP blockade on SDs generated by two widely used induction paradigms. We found that AP blockade using tetrodotoxin (TTX) restricted propagation of focally induced SDs, and significantly reduced the amplitude of neuronal depolarization, as well as its Ca2+ load. TTX also abolished the suppression of spont...

Brain function depends on segregation and integration of information processing in brain networks often separated by long-range anatomic connections. Neuronal oscillations orchestrate such distributed processing through transient amplitude and phase coupling, yet surprisingly, little is known about local network properties facilitating these functional connections. Here, we test whether criticality, a dynamical state characterized by scale-free oscillations, optimizes the capacity of neuronal networks to couple through amplitude or phase, and transfer information. We coupled in silico networks which exhibit oscillations in the α band (8–16 Hz), and varied excitatory and inhibitory connectivity. We found that phase coupling of oscillations emerges at criticality, and that amplitude coupling, as well as information transfer, are maximal when networks are critical. Importantly, regulating criticality through modulation of synaptic gain showed that critical dynamics, as opposed to a static ratio of excitatory ...

During sleep, the widespread coordination of neuronal oscillations across both cortical and subcortical brain regions is thought to support various physiological functions. However, how sleep-related activity within the brain's largest sensorimotor structure, the cerebellum, is multiplexed with well-described sleep-related mechanisms in regions such as the hippocampus remains unknown. We therefore simultaneously recorded from the dorsal hippocampus and three distinct regions of the cerebellum (Crus I, lobule VI, and lobules II/III) in male mice during natural sleep. Local field potential (LFP) oscillations were found to be coordinated between these structures in a sleep stage-specific manner. During non-REM sleep, prominent δ frequency coherence was observed between lobule VI and hippocampus, whereas non-REM-associated hippocampal sharp-wave ripple activity evoked discrete LFP modulation in all recorded cerebellar regions, with the shortest latency effects in lobule VI. We also describe discrete phasic sha...

Bodily rhythms appear as novel scaffolding mechanisms orchestrating the spatiotemporal organization of spontaneous brain activity. Here, we follow-up on the discovery of the gastric resting-state network ([Rebollo et al., 2018][1]), composed of brain regions in which the fMRI signal is phase-synchronized to the slow (0.05 Hz) electrical rhythm of the stomach. Using a larger sample size ( n = 63 human participants, both genders), we further characterize the anatomy and effect sizes of gastric-brain coupling across resting-state networks, a fine grained cortical parcellation, as well as along the main gradients of cortical organization. Most (67%) of the gastric network is included in the somato-motor-auditory (38%) and visual (29%) resting state networks (RSNs). Gastric brain coupling also occurs in the granular insula and, to a lesser extent, in the piriform cortex. Thus, all sensory and motor cortices corresponding to both exteroceptive and interoceptive modalities are coupled to the gastric rhythm during...

Failure of CNS neurons to mount a significant growth response after trauma contributes to chronic functional deficits after spinal cord injury. Activator and repressor screening of embryonic cortical neurons and retinal ganglion cells in vitro and transcriptional profiling of developing CNS neurons harvested in vivo have identified several candidates that stimulate robust axon growth in vitro and in vivo . Building on these studies, we sought to identify novel axon growth activators induced in the complex adult CNS environment in vivo . We transcriptionally profiled intact sprouting adult corticospinal neurons (CSNs) after contralateral pyramidotomy (PyX) in nogo receptor-1 knock-out mice and found that intact CSNs were enriched in genes in the 3-phosphoinositide degradation pathway, including six 5-phosphatases. We explored whether inositol polyphosphate-5-phosphatase K ( Inpp5k ) could enhance corticospinal tract (CST) axon growth in preclinical models of acute and chronic CNS trauma. Overexpression of I...

It is well established that glutamate plays an important role in drug-induced and cue-induced reinstatement of drug seeking. However, the role of glutamate in drug reward is unclear. In this study, we systemically evaluated the effects of multiple glutamate transporter (GLT) inhibitors on extracellular glutamate and dopamine (DA) in the nucleus accumbens (NAc), intravenous cocaine self-administration, intracranial brain-stimulation reward (BSR), and reinstatement of cocaine seeking in male and female rats. Among the five GLT inhibitors we tested, TFB-TBOA was the most potent. Microinjections of TFB-TBOA into the NAc, but not the ventral tegmental area (VTA), or dorsal striatum (DS), dose-dependently inhibited cocaine self-administration under fixed-ratio and progressive-ratio (PR) reinforcement schedules, shifted the cocaine dose–response curve downward, and inhibited intracranial BSR. Selective downregulation of astrocytic GLT-1 expression in the NAc by GLT-1 antisense oligonucleotides also inhibited coca...

Malfunctioning synaptic plasticity is one of the major mechanisms contributing to the development of chronic pain. We studied spike-timing dependent depression (tLTD) in the anterior cingulate cortex (ACC) of male mice, a brain region involved in processing emotional aspects of pain. tLTD onto layer 5 pyramidal neurons depended on postsynaptic calcium-influx through GluN2B-containing NMDARs and retrograde signaling via nitric oxide to reduce presynaptic release probability. After chronic constriction injury of the sciatic nerve, a model for neuropathic pain, tLTD was rapidly impaired; and this phenotype persisted even beyond the time of recovery from mechanical sensitization. Exclusion of GluN2B-containing NMDARs from the postsynaptic site specifically at projections from the anterior thalamus to the ACC caused the tLTD phenotype, whereas signaling downstream of nitric oxide synthesis remained intact. Thus, transient neuropathic pain can leave a permanent trace manifested in the disturbance of synaptic pla...

During neuronal migration, forces generated by cytoplasmic dynein yank on microtubules extending from the centrosome into the leading process and move the nucleus along microtubules that extend behind the centrosome. Scaffolds, such as radial glia, guide neuronal migration outward from the ventricles, but little is known about the internal machinery that ensures that the soma migrates along its proper path rather than moving backward or off the path. Here we report that depletion of KIFC1, a minus-end-directed kinesin called HSET in humans, causes neurons to migrate off their appropriate path, suggesting that this molecular motor is what ensures fidelity of the trajectory of migration. For these studies, we used rat migratory neurons in vitro and developing mouse brain in vivo , together with RNA interference and ectopic expression of mutant forms of KIFC1. We found that crosslinking of microtubules into a nonsliding mode by KIFC1 is necessary for dynein-driven forces to achieve sufficient traction to thru...

The high sensitivity of night vision requires that rod photoreceptors reliably and reproducibly signal the absorption of single photons, a process that depends on tight regulation of intracellular cGMP concentration through the phototransduction cascade. Here in the mouse (Mus musculus), we studied a single-site D167A mutation of the gene for the α subunit of rod photoreceptor phosphodiesterase (PDEA), made with the aim of removing a noncatalytic binding site for cGMP. This mutation unexpectedly eliminated nearly all PDEA expression and reduced expression of the β subunit (PDEB) to ∼5%-10% of WT. The remaining PDE had nearly normal specific activity; degeneration was slow, with 50%-60% of rods remaining after 6 months. Responses were larger and more sensitive than normal but slower in rise and decay, probably from slower dark turnover of cGMP. Remarkably, responses became much less reproducible than WT, with response variance increasing for amplitude by over 10-fold, and for latency and time-to-peak by >10...