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...

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...

During multisensory speech perception, slow δ oscillations (∼1–3 Hz) in the listener's brain synchronize with the speech signal, likely engaging in speech signal decomposition. Notable fluctuations in the speech amplitude envelope, resounding speaker prosody, temporally align with articulatory and body gestures and both provide complementary sensations that temporally structure speech. Further, δ oscillations in the left motor cortex seem to align with speech and musical beats, suggesting their possible role in the temporal structuring of (quasi)-rhythmic stimulation. We extended the role of δ oscillations to audiovisual asynchrony detection as a test case of the temporal analysis of multisensory prosody fluctuations in speech. We recorded Electroencephalograph (EEG) responses in an audiovisual asynchrony detection task while participants watched videos of a speaker. We filtered the speech signal to remove verbal content and examined how visual and auditory prosodic features temporally (mis-)align. Results...

Theta oscillations are key brain rhythm involved in memory formation, sensorimotor integration, and control of locomotion and behavioral states. Generation and spatiotemporal synchronization of theta oscillations rely on interactions between brain nuclei forming a large neural network, which includes pontine nucleus incertus (NI). Here we identified distinct populations of NI neurons, based on the relationship of their firing to hippocampal waves, with a special focus on theta oscillations, and the direction and type of interaction with the medial septum (MS) in male, urethane-anesthetized rats. By recording NI neuronal firing and hippocampal LFP, we described NI neurons that fire action potentials in a theta phase-independent or theta phase-locked and delta wave-independent or delta wave-locked manner. Among hippocampal activity-independent NI neurons, irregular, slow-firing, and regular, fast-firing cells were observed, while hippocampal oscillation-/wave-locked NI neurons were of a bursting or nonbursti...

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...

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...

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...

Hemalatha Muralidharan, Shrobona Guha, Kiran Madugula, Ankita Patil, Sarah A. Bennison, et al. (see pages [2149–2165][1]) The first cells of the developing nervous system are radial glial cells, the progenitors of neurons and astrocytes. These elongated cells contact both the ventricular (apical

Individuals with chronic pain often experience depression, resulting in greater disability and a worse prognosis than either condition alone ([Goesling et al., 2013][1]). The prevalence of depression among individuals experiencing neuropathic pain, one type of chronic pain caused by injury of the

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...