Increasing loss of structure and function of neurons and decline in cognitive function is commonly seen during the progression of neurologic diseases, although the causes and initial symptoms of individual diseases are distinct. This observation suggests a convergence of common degenerative features. In myotonic dystrophy type 1 (DM1), the expression of expanded CUG RNA induces neurotransmission dysfunction before axon and dendrite degeneration and reduced MBNL2 expression associated with aberrant alternative splicing. The role of loss of function of MBNL2 in the pathogenesis of neurodegeneration and the causal mechanism of neurodegeneration-reduced expression of MBNL2 remain elusive. Here, we show that increased MBNL2 expression is associated with neuronal maturation and required for neuronal morphogenesis and the fetal to adult developmental transition of RNA processing. Neurodegenerative conditions including NMDA receptor (NMDAR)-mediated excitotoxicity and dysregulated calcium homeostasis triggered nuc...

Sotatsu Tonomura and Jianguo G. Gu (see pages [4980–4994][1]) In myelinated axons, ion channels involved in action potential propagation are located exclusively at nodes of Ranvier. In neuronal somata and unmyelinated axons, voltage-gated potassium channels (VGKCs) open during action potentials

Opioid withdrawal involves the manifestation of motivational and somatic symptoms. However, the brain structures that are involved in the expression of different opioid withdrawal signs remain unclear. We induced opioid dependence by repeatedly injecting escalating heroin doses in male and female C57BL/6J mice. We assessed hyperalgesia during spontaneous heroin withdrawal and somatic signs of withdrawal that was precipitated by the preferential µ-opioid receptor antagonist naloxone. Heroin-treated mice exhibited significantly higher hyperalgesia and somatic signs than saline-treated mice. Following behavioral assessment, we measured regional changes in brain activity by automated the counting of c-Fos expression (a marker of cellular activity). Using Principal Component Analysis, we determined the association between behavior (hyperalgesia and somatic signs of withdrawal) and c-Fos expression in different brain regions. Hyperalgesia was associated with c-Fos expression in the lateral hypothalamus, central ...

Speech is an intrinsically multisensory signal and seeing the speaker's lips forms a cornerstone of communication in acoustically impoverished environments. Still, it remains unclear how the brain exploits visual speech for comprehension. Previous work debated whether lip signals are mainly processed along the auditory pathways or whether the visual system directly implements speech-related processes. To probe this, we systematically characterized dynamic representations of multiple acoustic and visual speech-derived features in source localized MEG recordings that were obtained while participants listened to speech or viewed silent speech. Using a mutual-information framework we provide a comprehensive assessment of how well temporal and occipital cortices reflect the physically presented signals and unique aspects of acoustic features that were physically absent but may be critical for comprehension. Our results demonstrate that both cortices feature a functionally specific form of multisensory restorati...

How do animals experience brain manipulations? Optogenetics has allowed us to manipulate selectively and interrogate neural circuits underlying brain function in health and disease. However, little is known about whether mice can detect and learn from arbitrary optogenetic perturbations from a wide range of brain regions to guide behavior. To address this issue, mice were trained to report optogenetic brain perturbations to obtain rewards and avoid punishments. Here we found that mice can perceive optogenetic manipulations regardless of the perturbed brain area, rewarding effects, or the stimulation of glutamatergic, GABAergic, and dopaminergic cell types. We named this phenomenon optoception, a perceptible signal internally generated from perturbing the brain, as occurs with interoception. Using optoception, mice can learn to execute two different sets of instructions based on the laser frequency. Importantly, optoception can occur either activating or silencing a single cell type. Moreover, stimulation o...

The ability to encode and retrieve contextual information is an inherent feature of episodic memory that starts to develop during childhood. The postrhinal cortex, an area of the parahippocampal region, has a crucial role in encoding object-space information and translating egocentric to allocentric representation of local space. The strong connectivity of POR with the adjacent entorhinal cortex, and consequently the hippocampus, suggests that the development of these connections could support the postnatal development of contextual memory. Here, we report that postrhinal cortex projections of the rat develop progressively from the first to the third postnatal week starting in the medial entorhinal cortex before spreading to the lateral entorhinal cortex. The increased spread and complexity of postrhinal axonal distributions is accompanied by an increased complexity of entorhinal dendritic trees and an increase of postrhinal – entorhinal synapses, which supports a gradual maturation in functional activity....

Metabolic state can alter olfactory sensitivity, but it is unknown if 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 CRIPSR mice confirmed increased excitability due the targeted loss of Kv1.3 channels, which resulted in a less negative resting membrane potential, enhanced action potential firing, and insensitivity to the selective channel blocker margatoxin. CRISPR mice exhibited enhanced odor discrimination using a habituation/dishabituation paradigm. CRISPR mice were challenged for 25 weeks with a moderately high-fat 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 tissue, cleared a glucose challe...

Schemata enhance memory formation for related novel information. This is true even when this information is neutral with respect to schema-driven expectations. This assimilation of novel information into schemata has been attributed to more effective organizational processing that leads to more referential connections with the activated associative schema network. Animal data suggest that systems consolidation of novel assimilated information is also accelerated. In the current study, we used both multivariate and univariate fMRI analyses to provide further support for these proposals and to elucidate the neural underpinning of these processes. 28 Participants (5 male) over-learned fictitious schemata for seven weeks and then encoded novel related and control facts in the scanner. These facts were retrieved both immediately and two weeks later, also in the scanner. Our results conceptually replicate previous findings with respect to enhanced vmPFC-hippocampus coupling during encoding of novel related infor...

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 non-conflicting 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 th...

Neural substrates of evidence accumulation have been a central issue in decision-making studies because of the prominent success of the accumulation model in explaining a wide range of perceptual decision making. Since accumulation-shaped activities have been found in multiple brain regions, which are called accumulators, questions regarding functional relations among these accumulators are emerging. This study employed the deconvolution method of functional magnetic resonance imaging (fMRI) signals from human male and female participants during object-category decision tasks, taking advantage of the whole-brain coverage of fMRI with improved availability of temporal information of the deconvolved activity. We detected the accumulation activity in many non-category-selective regions (NCSRs) over the frontal, parietal, and temporal lobes as well as category-selective regions (CSRs) of the categorization task. Importantly, the frontal regions mostly showed activity peaks matching the decision timing (classif...