Metabolic state can alter olfactory sensitivity, but it is unknown whether the activity of the olfactory bulb (OB) may fine tune metabolic homeostasis. Our objective was to use CRISPR gene editing in male and female mice to enhance the excitability of mitral/tufted projection neurons (M/TCs) of the OB to test for improved metabolic health. Ex vivo slice recordings of MCs in CRISPR mice confirmed increased excitability due the targeted loss of Kv1.3 channels, which resulted in a less negative resting membrane potential (RMP), enhanced action potential (AP) firing, and insensitivity to the selective channel blocker margatoxin (MgTx). CRISPR mice exhibited enhanced odor discrimination using a habituation/dishabituation paradigm. CRISPR mice were challenged for 25 weeks with a moderately high-fat (MHF) diet, and compared with littermate controls, male mice were resistance to diet-induced obesity (DIO). Female mice did not exhibit DIO. CRISPR male mice gained less body weight, accumulated less white adipose tis...

While conflict between incompatible goals has well-known effects on actions, in many situations the same action may produce harmful or beneficial consequences during different periods in a nonconflicting manner, e.g., crossing the street during a red or green light. To avoid harm, subjects must be cautious to inhibit the action specifically when it is punished, as in passive avoidance, but act when it is beneficial, as in active avoidance or active approach. In mice of both sexes performing a signaled action to avoid harm or obtain reward, we found that addition of a new rule that punishes the action when it occurs unsignaled delays the timing of the signaled action in an apparent sign of increased caution. Caution depended on task signaling, contingency, and reinforcement type. Interestingly, caution became persistent when the signaled action was avoidance motivated by danger but was only transient when it was approach motivated by reward. Although caution is represented by the activity of neurons in the ...

Shiyi Li, Shuangmei Ma, Danyang Wang, Hejing Zhang, Yunzhu Li, et al. (see pages [5930–5943][1]) Cooperation allows groups to gain rewards that would be difficult to obtain by individuals working alone. To sustain cooperation, groups often punish members that try to reap rewards without

When making a turn at a familiar intersection, we know what items and landmarks will come into view. These perceptual expectations, or predictions, come from our knowledge of the context; however, it is unclear how memory and perceptual systems interact to support the prediction and reactivation of sensory details in cortex. To address this, human participants learned the spatial layout of animals positioned in a cross maze. During fMRI, participants of both sexes navigated between animals to reach a target, and in the process saw a predictable sequence of five animal images. Critically, to isolate activity patterns related to item predictions, rather than bottom-up inputs, one-fourth of trials ended early, with a blank screen presented instead. Using multivariate pattern similarity analysis, we reveal that activity patterns in early visual cortex, posterior medial regions, and the posterior hippocampus showed greater similarity when seeing the same item compared with different items. Further, item effects...

The posteromedial cortex (PMC) is a major hub of the brain's default mode network, and is implicated in a broad range of internally driven cognitions, including visuospatial working memory. However, its precise contribution to these cognitive processes remains unclear. Using MEG, we measured PMC activity in healthy human participants (young adults of both sexes) while they performed a visuospatial working memory task. Multivariate pattern classification analyses revealed stimulus-related information during encoding and retrieval in a set of a priori defined cortical ROIs, including prefrontal, occipital, and ventrotemporal cortices, in addition to PMC. We measured the extent to which this stimulus information was exchanged between areas in an information flow analysis, measuring Granger-causal relationships between areas over time. Consistent with the visual nature of the task, information from occipital cortex shaped other regions across most epochs. However, the PMC shaped object representations in occip...

Thyroid hormone (TH) controls the timely differentiation of oligodendrocytes (OLs), and its deficiency can delay myelin development and cause mental retardation. Previous studies showed that the active TH T3 is converted from its prohormone T4 by the selenoprotein DIO2, whose mRNA is primarily expressed in astrocytes in the CNS. In the present study, we discovered that SECISBP2L is highly expressed in differentiating OLs and is required for DIO2 translation. Conditional knock-out (CKO) of Secisbp2l in OL lineage resulted in a decreased level of DIO2 and T3, accompanied by impaired OL differentiation, hypomyelination and motor deficits in both sexes of mice. Moreover, the defective differentiation of OLs in Secisbp2l mutants can be alleviated by T3 or its analog, but not the prohormone T4. The present study has provided strong evidence for the autonomous regulation of OL differentiation by its intrinsic T3 production mediated by the novel SECISBP2L-DIO2-T3 pathway during myelin development. SIGNIFICANCE ST...

The nervous system is under tight energy constraints and must represent information efficiently. This is particularly relevant in the dorsal part of the medial superior temporal area (MSTd) in primates where neurons encode complex motion patterns to support a variety of behaviors. A sparse decomposition model based on a dimensionality reduction principle known as non-negative matrix factorization (NMF) was previously shown to account for a wide range of monkey MSTd visual response properties. This model resulted in sparse, parts-based representations that could be regarded as basis flow fields, a linear superposition of which accurately reconstructed the input stimuli. This model provided evidence that the seemingly complex response properties of MSTd may be a by-product of MSTd neurons performing dimensionality reduction on their input. However, an open question is how a neural circuit could carry out this function. In the current study, we propose a spiking neural network (SNN) model of MSTd based on evo...

Peripheral somatosensory neurons innervate the skin and sense the environment. Whereas many studies focus on initial axon outgrowth and pathfinding, how signaling pathways contribute to maintenance of the established axon arbors and terminals within the skin is largely unknown. This question is particularly relevant to the many types of neuropathies that affect mature neuronal arbors. We show that a receptor tyrosine kinase (RTK), c-Kit, contributes to maintenance, but not initial development, of cutaneous axons in the larval zebrafish before sex determination. Downregulation of Kit signaling rapidly induced retraction of established axon terminals in the skin and a reduction in axonal density. Conversely, misexpression of c-Kit ligand in the skin in larval zebrafish induced increases in local sensory axon density, suggesting an important role for Kit signaling in cutaneous axon maintenance. We found Src family kinases (SFKs) act directly downstream to mediate Kit’s role in regulating cutaneous axon densit...

To avoid information loss, the auditory system must adapt the broad dynamic range of natural sounds to the restricted dynamic range of auditory nerve fibers. How it solves this dynamic range problem is not fully understood. Recent electrophysiological studies showed that dynamic-range adaptation occurs at the auditory-nerve level, but the amount of adaptation found was insufficient to prevent information loss. We used the physiological matlab® Auditory Periphery model to study the contribution of efferent reflexes to dynamic range adaptation. Simulating the healthy human auditory periphery provided adaptation predictions that suggest that the acoustic reflex shifts rate-level functions towards a given context level and the medial olivo-cochlear reflex sharpens the response of nerve fibers around that context level. A simulator of hearing was created to decode model-predicted firing of the auditory nerve back into an acoustic signal, for use in psychophysical tasks. Speech reception thresholds in noise obta...

The activation of self-destructive cellular programs helps sculpt the nervous system during development, but the molecular mechanisms used are not fully understood. Prior studies have investigated the role of the APP in the developmental degeneration of sensory neurons with contradictory results. In this work, we sought to elucidate the impact of APP deletion in the development of the sensory nervous system in vivo and in vitro. Our in vivo data show an increase in the number of sciatic nerve axons in adult male and female APP-null mice, consistent with the hypothesis that APP plays a pro-degenerative role in the development of peripheral axons. In vitro , we show that genetic deletion of APP delays axonal degeneration triggered by nerve growth factor deprivation, indicating that APP does play a pro-degenerative role. Interestingly, APP depletion does not affect caspase-3 levels but significantly attenuates the rise of axoplasmic Ca2+ that occurs during degeneration. We examined intracellular Ca2+ mechanis...