Alcohol dependence can result in long-lasting deficits to decision-making and action control. Neurobiological investigations have identified orbitofrontal cortex (OFC) as important for outcome-related contributions to goal-directed actions during decision-making. Prior work has shown that alcohol dependence induces long-lasting changes to OFC function that persist into protracted withdrawal and disrupts goal-directed control over actions. However, it is unclear whether these changes in function alter representation of action and outcome-related neural activity in OFC. Here, we used the well-validated chronic intermittent ethanol (CIE) exposure and withdrawal procedure to model alcohol dependence in mice and performed in vivo extracellular recordings during an instrumental task in which lever-press actions made for a food outcome. We found alcohol dependence disrupted goal-directed action control and increased OFC activity associated with lever-pressing but decreased OFC activity during outcome-related epoc...

Where are we now, 1 year after eNeuro launched an initiative to encourage the use of estimation statistics in neuroscience? We started to attract attention to estimation statistics in August 2019 with an editorial (Bernard, 2019) and opinion paper (Calin-Jageman and Cumming, 2019). In February 2020, I asked Reviewing Editors to identify papers that could benefit from converting to estimation statistics. One hundred were thus identified. And, overall in 2020, 52 published papers included estimation statistics in their analyses! One of the earliest papers to include estimation statistics was from my own laboratory because I was determined to be sure for myself that this was a feasible step to take. So, thank you all for making this initiative a success. Using estimation statistics, in addition to the classical significance testing (and the p value), is not a constraint. The feedback we get from authors who did it is nothing but positive. The display of results is much clearer, and the effect sizes can be se...

Mitral/tufted (MT) cells of the olfactory bulb (OB) show diverse temporal responses to odorant stimulation that are thought to encode odor information. Much of this diversity is thought to arise from inhibitory OB circuits, but the dynamics of excitatory input to MT cells, which is driven in a feedforward manner by sensory afferents, may also be important. To examine the contribution of excitatory input dynamics to generating temporal diversity in MT cells, we imaged glutamate signaling onto MT cell dendrites in anesthetized and awake mice. We found surprising diversity in the temporal dynamics of these signals. Inhalation-linked glutamate transients were variable in onset latency and duration, and in awake mice the degree of coupling to inhalation varied substantially with odorant identity and concentration. Successive inhalations of odorant produced nonlinear changes in glutamate signaling that included facilitating, adapting and suppressive responses and which varied with odorant identity and concentrat...

Prevalence of metabolic disturbances is higher among individuals with neurodevelopmental disorders (NDDs), yet this association has been largely overlooked. Investigation into human disease remains challenging, as a complete pathophysiological understanding relies on accurate modeling and highly controlled variables. Genetically engineered mouse models are widely used to gain insight into the biology of human NDDs, but research focus has been on behavioral and neurophysiological abnormalities. Such models not only allow for evaluating usefulness in reproducing human features, including similarities and discrepancies with rodent phenotypes, but they also represent a unique opportunity to observe and quantify novel anomalies. Here, we present the first characterization and comparison of basal metabolism in three mouse models of NDDs, namely, Down syndrome (DS; Dp(16)Yey/+ mice), 16p11.2 deletion syndrome (16pDel; 16p11.2df/+ mice), and fragile X syndrome [FXS; Fmr1 knock-out (KO) mice] and their wild-type (W...

GABAergic projections neurons of the substantia nigra reticulata (SNr), through an extensive network of dendritic arbors and axon collaterals, provide robust inhibitory input to neighboring dopaminergic neurons in the substantia nigra compacta (SNc). Angiotensin-II (Ang-II) receptor signaling increases SNc dopaminergic neuronal sensitivity to insult, thus rendering these cells susceptible to dysfunction and destruction. However, the mechanisms by which Ang-II regulates SNc dopaminergic neuronal activity are unclear. Given the complex relationship between SN dopaminergic and GABAergic neurons, we hypothesized that Ang-II could regulate SNc dopaminergic neuronal activity directly and indirectly by modulating SNr GABAergic neurotransmission. Here, using transgenic mice, slice electrophysiology, and optogenetics, we provide evidence of an AT1 receptor-mediated signaling mechanism in SNr GABAergic neurons where Ang-II suppresses electrically-evoked neuronal output by facilitating postsynaptic GABAA receptors (G...

The objective of this review of the literature is to summarize the physiology of orofacial pain in dentistry, particularly physiology of the pain pathway and molecular mechanisms on pathophysiology of pain, on account of new insights into classification of orofacial pain related diseases. This article will also focus on possible mechanisms of neuropathic orofacial pain which is distinguished from other types of pain.

Numerous studies have proposed that specific brain activity statistics provide evidence that the brain operates at a critical point, which could have implications for the brain’s information processing capabilities. A recent paper reported that identical scalings and criticality signatures arise in a variety of different neural systems (neural cultures, cortical slices, anesthetized or awake brains, across both reptiles and mammals). The diversity of these states calls into question the claimed role of criticality in information processing. We analyze the methodology used to assess criticality and replicate this analysis for spike trains of two non-critical systems. These two non-critical systems pass all the tests used to assess criticality in the aforementioned recent paper. This analysis provides a crucial control (which is absent from the original study) and suggests that the methodology used may not be sufficient to establish that a system operates at criticality. Hence whether the brain operates at c...

Stomatin-like protein-3 (STOML3) is an integral membrane protein expressed in the cilia of olfactory sensory neurons, but its functional role in this cell type has never been addressed. STOML3 is also expressed in dorsal root ganglia neurons, where it has been shown to be required for normal touch sensation. Here, we extended previous results indicating that STOML3 is mainly expressed in the knob and proximal cilia of olfactory sensory neurons. We additionally showed that mice lacking STOML3 have a morphologically normal olfactory epithelium. Due to its presence in the cilia, together with known olfactory transduction components, we hypothesized that STOML3 could be involved in modulating odorant responses in olfactory sensory neurons. To investigate the functional role of STOML3, we performed loose patch recordings from wild type and Stoml3 KO olfactory sensory neurons. We found that spontaneous mean firing activity was lower with additional shift in interspike intervals distributions in Stoml3 KOs compar...

Vision begins when light is captured by the outer segment organelle of photoreceptor cells in the retina. Outer segments are modified cilia filled with hundreds of flattened disc-shaped membranes. Disc membranes are separated from the surrounding plasma membrane and each membrane type has unique protein components. The mechanisms underlying this protein sorting remain entirely unknown. In this study, we investigated the outer segment delivery of the rod cyclic nucleotide-gated (CNG) channel, which is located in the outer segment plasma membrane where it mediates the electrical response to light. Using Xenopus and mouse models of both sexes, we now show that the targeted delivery of the CNG channel to the outer segment utilizes the conventional secretory pathway, including protein processing in both ER and Golgi, and requires pre-assembly of its constituent α1 and β1 subunits. We further demonstrate that the N-terminal GARP domain of CNGβ1 contains two distinct functional regions. The glutamic acid-rich reg...

Interneurons contribute to the complexity of neural circuits and maintenance of normal brain function. Rodent interneurons originate in embryonic ganglionic eminences, but developmental origins in other species are less understood. Here, we show that transcription factor expression patterns in porcine embryonic subpallium are similar to rodents, delineating a distinct medial ganglionic eminence (MGE) progenitor domain. On the basis of Nkx2.1, Lhx6 and Dlx2 expression, in vitro differentiation into neurons expressing GABA and robust migratory capacity in explant assays, we propose that cortical and hippocampal interneurons originate from a porcine MGE region. Following xenotransplantation into adult male and female rat hippocampus, we further demonstrate that porcine MGE progenitors, like those from rodents, migrate and differentiate into morphologically distinct interneurons expressing GABA. Our findings reveal that basic rules for interneuron development are conserved across species, and that porcine embr...