One consequence of the opioid epidemic are lasting neurodevelopmental sequelae afflicting adolescents exposed to opioids in the womb. A translationally relevant and developmentally accurate preclinical model is needed to understand the behavioral, circuit, network, and molecular abnormalities resulting from this exposure. By employing a novel preclinical model of perinatal fentanyl exposure, our data reveal that fentanyl has several dose-dependent, developmental consequences to somatosensory function and behavior. Newborn male and female mice exhibit signs of withdrawal and sensory-related deficits that extend at least to adolescence. As fentanyl exposure does not affect dams' health or maternal behavior, these effects result from the direct actions of perinatal fentanyl on the pups' developing brain. At adolescence, exposed mice exhibit reduced adaptation to sensory stimuli, and a corresponding impairment in primary somatosensory (S1) function. In vitro electrophysiology demonstrates a long-lasting reduct...

Locomotion, scratching, and stabilization of the body orientation in space are basic motor functions which are critically important for animal survival. Their execution requires coordinated activity of muscles located in the left and right halves of the body. Commissural interneurons (CINs) are critical elements of the neuronal networks underlying the left–right motor coordination. V0 interneurons (characterized by the early expression of the transcription factor Dbx1) contain a major class of CINs in the spinal cord (excitatory, V0V; inhibitory, V0D), and a small subpopulation of excitatory ipsilaterally projecting interneurons. The role of V0 CINs in left–right coordination during forward locomotion was demonstrated earlier. Here, to reveal the role of glutamatergic V0 and other V0 subpopulations in control of backward locomotion, scratching, righting behavior, and postural corrections, kinematics of these movements performed by wild-type mice and knock-out mice with glutamatergic V0 or all V0 interneuro...

Research in functional neuroimaging has suggested that category-selective regions of visual cortex, including the ventral temporal cortex (VTC), can be reactivated endogenously through imagery and recall. Face representation in the monkey face-patch system has been well studied and is an attractive domain in which to explore these processes in humans. The VTCs of 8 human subjects (4 female) undergoing invasive monitoring for epilepsy surgery were implanted with microelectrodes. Most (26 of 33) category-selective units showed specificity for face stimuli. Different face exemplars evoked consistent and discriminable responses in the population of units sampled. During free recall, face-selective units preferentially reactivated in the absence of visual stimulation during a 2 s window preceding face recall events. Furthermore, we show that in at least 1 subject, the identity of the recalled face could be predicted by comparing activity preceding recall events to activity evoked by visual stimulation. We show ...

Jessica N. Little, Katrina C. McNeely, Nadine Michel, Christopher J. Bott, Kaela S. Lettieri, et al. (see pages [3344–3365][1]) Early in nervous system development, neural stem cells (NSCs) proliferate through symmetric divisions that produce two daughter stem cells. Later, asymmetric divisions

Golgi cells, together with granule cells and mossy fibers, form a neuronal microcircuit regulating information transfer at the cerebellum input stage. Despite theoretical predictions, little was known about long-term synaptic plasticity at Golgi cell synapses. Here, we have used whole-cell patch-clamp recordings and calcium imaging to investigate long-term synaptic plasticity at excitatory synapses impinging on Golgi cells. In acute mouse cerebellar slices, mossy fiber theta-burst stimulation (TBS) could induce either long-term potentiation (LTP) or long-term depression (LTD) at mossy fiber-Golgi cell and granule cell-Golgi cell synapses. This synaptic plasticity showed a peculiar voltage dependence, with LTD or LTP being favored when TBS induction occurred at depolarized or hyperpolarized potentials, respectively. LTP required, in addition to NMDA channels, activation of T-type Ca2+ channels, while LTD required uniquely activation of L-type Ca2+ channels. Notably, the voltage dependence of plasticity at t...

Rod photoreceptors can be saturated by exposure to bright background light, so that no flash superimposed on the background can elicit a detectable response. This phenomenon, called increment saturation, was first demonstrated psychophysically by Aguilar and Stiles and has since been shown in many studies to occur in single rods. Recent experiments indicate, however, that rods may be able to avoid saturation under some conditions of illumination. We now show in ex vivo electroretinogram and single-cell recordings that in continuous and prolonged exposure even to very bright light, the rods of mice from both sexes recover as much as 15% of their dark current and that responses can persist for hours. In parallel to recovery of outer segment current is an ∼10-fold increase in the sensitivity of rod photoresponses. This recovery is decreased in transgenic mice with reduced light-dependent translocation of the G protein transducin. The reduction in outer-segment transducin together with a novel mechanism of vis...

Sound detection happens in the inner ear via the mechanical deflection of the hair bundle of cochlear hair cells. The hair bundle is an apical specialization consisting of actin-filled membrane protrusions (called stereocilia) connected by tip links (TLs) that transfer the deflection force to gate the mechanotransduction channels. Here, we identified the hearing loss-associated Loxhd1/DFNB77 gene as being required for the mechanotransduction process. LOXHD1 consists of 15 polycystin lipoxygenase α-toxin (PLAT) repeats, which in other proteins can bind lipids and proteins. LOXHD1 was distributed along the length of the stereocilia. Two LOXHD1 mouse models with mutations in the 10th PLAT repeat exhibited mechanotransduction defects (in both sexes). While mechanotransduction currents in mutant inner hair cells (IHCs) were similar to wild-type levels in the first postnatal week, they were severely affected by postnatal day 11. The onset of the mechanotransduction phenotype was consistent with the temporal prog...

To build the brain, embryonic neural stem cells (NSCs) tightly regulate their cell divisions, undergoing a polarized form of cytokinesis that is poorly understood. Cytokinetic abscission is mediated by the midbody to sever the daughter cells at the apical membrane. In cell lines, the coiled-coil protein Cep55 was reported to be required for abscission. Mutations of Cep55 in humans cause a variety of cortical malformations. However, its role in the specialized divisions of NSCs is unclear. Here, we elucidate the roles of Cep55 in abscission and brain development. KO of Cep55 in mice causes abscission defects in neural and non-neural cell types, and postnatal lethality. The brain is disproportionately affected, with severe microcephaly at birth. Quantitative analyses of abscission in fixed and live cortical NSCs show that Cep55 acts to increase the speed and success rate of abscission, by facilitating ESCRT recruitment and timely microtubule disassembly. However, most NSCs complete abscission successfully in...

The cerebellum processes neural signals related to rewarding and aversive stimuli, suggesting that the cerebellum supports nonmotor functions in cognitive and emotional domains. Catecholamines are a class of neuromodulatory neurotransmitters well known for encoding such salient stimuli. Catecholaminergic modulation of classical cerebellar functions have been demonstrated. However, a role for cerebellar catecholamines in modulating cerebellar nonmotor functions is unknown. Using biochemical methods in male mice, we comprehensively mapped TH+ fibers throughout the entire cerebellum and known precerebellar nuclei. Using electrochemical (fast scan cyclic voltammetry), and viral/genetic methods to selectively delete Th in fibers innervating the lateral cerebellar nucleus (LCN), we interrogated sources and functional roles of catecholamines innervating the LCN, which is known for its role in supporting cognition. The LCN has the most TH+ fibers in cerebellum, as well as the most change in rostrocaudal expression...