During aging, skeletal muscles become atrophic and lose contractile force. Aging can also impact the neuromuscular junction (NMJ), a synapse that transmits signals from motoneurons to muscle fibers to control muscle contraction. However, in contrast to muscle aging that has been studied extensively, less is known about the molecular mechanisms of NMJ aging although its structure and function are impaired in aged animals. To this end, we performed RNA sequencing (RNA-seq) analysis to identify genes whose expression in synapse-rich region is altered. Gene ontology (GO) analysis highlighted genes relating to nuclear structure or function. In particular, lamin A/C, an intermediate filament protein critical for the interphase nuclear architecture, was reduced. Remarkably, mutation of lamin A/C in muscles or motoneurons had no effect on NMJ formation in either sex of mice, but the muscle mutation caused progressive denervation, acetylcholine receptor (AChR) cluster fragmentation, and neuromuscular dysfunction. I...

The hippocampal formation encodes maps of space and a key question in neuroscience is whether its spatial coding principles also provide a universal metric for the organization of nonspatial, conceptual information. Previous work demonstrated directional coding during navigation through a continuous stimulus feature space as well as mapping of distances in a feature space that was relevant for concept learning. Here we provide the first unambiguous evidence for a hippocampal representation of the actual concept space, by showing that the hippocampal distance signal selectively reflects the mapping of specifically conceptually relevant rather than of all feature dimensions. During fMRI scanning of 32 human participants (21 females), we presented everyday objects, which had beforehand been associated with specific values on three continuous feature dimensions. Crucially, only two dimensions were relevant to prior concept learning. We find that hippocampal responses to the objects reflect their relative dista...

Optimal attention performance requires cholinergic modulation of corticothalamic neurons in the prefrontal cortex. These pyramidal cells express specialized nicotinic acetylcholine receptors containing the α5 subunit encoded by Chrna5 . Disruption of this gene impairs attention, but the advantage α5 confers on endogenous cholinergic signaling is unknown. To ascertain this underlying mechanism, we used optogenetics to stimulate cholinergic afferents in prefrontal cortex brain slices from compound-transgenic wild-type and Chrna5 knock-out mice of both sexes. These electrophysiological experiments identify that Chrna5 is critical for the rapid onset of the postsynaptic cholinergic response. Loss of α5 slows cholinergic excitation and delays its peak, and these effects are observed in two different optogenetic mouse lines. Disruption of Chrna5 does not otherwise perturb the magnitude of the response, which remains strongly mediated by nicotinic receptors and tightly controlled by autoinhibition via muscarinic ...

Although the decisions of our daily lives often occur in the context of temporal and reward structures, the impact of such regularities on decision-making strategy is poorly understood. Here, to explore how temporal and reward context modulate strategy, we trained 2 male rhesus monkeys to perform a novel perceptual decision-making task with asymmetric rewards and time-varying evidence reliability. To model the choice and response time patterns, we developed a computational framework for fitting generalized drift-diffusion models, which flexibly accommodate diverse evidence accumulation strategies. We found that a dynamic urgency signal and leaky integration, in combination with two independent forms of reward biases, best capture behavior. We also tested how temporal structure influences urgency by systematically manipulating the temporal structure of sensory evidence, and found that the time course of urgency was affected by temporal context. Overall, our approach identified key components of cognitive me...

David B. Kastner, Anna K. Gillespie, Peter Dayan, and Loren M. Frank (see pages [7311–7317][1]) Many behavioral tasks have been developed to identify brain areas, genes, and molecular pathways involved in cognitive processes and neurological conditions. For example, the open-field test is used

Subjective tinnitus is the conscious perception of sound in the absence of any acoustic source. The literature suggests various tinnitus mechanisms, most of which invoke changes in spontaneous firing rates of central auditory neurons resulting from modification of neural gain. Here, we present an alternative model based on evidence that tinnitus is: (1) rare in people who are congenitally deaf, (2) common in people with acquired deafness, and (3) potentially suppressed by active cochlear implants used for hearing restoration. We propose that tinnitus can only develop after fast auditory fiber activity has stimulated the synapse formation between fast-spiking parvalbumin positive (PV+) interneurons and projecting neurons in the ascending auditory path and coactivated frontostriatal networks after hearing onset. Thereafter, fast auditory fiber activity promotes feedforward and feedback inhibition mediated by PV+ interneuron activity in auditory-specific circuits. This inhibitory network enables enhanced stim...

17β-Estradiol (E2) is produced from androgens via the action of the enzyme aromatase. E2 is known to be made in neurons in the brain, but the functions of neuron-derived E2 in the ischemic brain are unclear. Here, we used a forebrain neuron-specific aromatase KO (FBN-ARO-KO) mouse model to deplete neuron-derived E2 in the forebrain and determine its roles after global cerebral ischemia. We demonstrated that ovariectomized female FBN-ARO-KO mice exhibited significantly attenuated astrocyte activation, astrocytic aromatization, and decreased hippocampal E2 levels compared with FLOX mice. Furthermore, FBN-ARO-KO mice had exacerbated neuronal damage and worse cognitive dysfunction after global cerebral ischemia. Similar results were observed in intact male mice. RNA-seq analysis revealed alterations in pathways and genes associated with astrocyte activation, neuroinflammation, and oxidative stress in FBN-ARO-KO mice. The compromised astrocyte activation in FBN-ARO-KO mice was associated with robust downregulat...

Humans learn quickly which actions cause them harm. As social beings, we also need to learn to avoid actions that hurt others. It is currently unknown whether humans are as good at learning to avoid others' harm (prosocial learning) as they are at learning to avoid self-harm (self-relevant learning). Moreover, it remains unclear how the neural mechanisms of prosocial learning differ from those of self-relevant learning. In this fMRI study, 96 male human participants learned to avoid painful stimuli either for themselves or for another individual. We found that participants performed more optimally when learning for the other than for themselves. Computational modeling revealed that this could be explained by an increased sensitivity to subjective values of choice alternatives during prosocial learning. Increased value sensitivity was further associated with empathic traits. On the neural level, higher value sensitivity during prosocial learning was associated with stronger engagement of the ventromedial PF...

Maladaptation to stress is a critical risk factor in stress-related disorders, such as major depression and post-traumatic stress disorder (PTSD). Dopamine signaling in the nucleus accumbens (NAc) has been shown to modulate behavior by reinforcing learning and evading aversive stimuli, which are important for the survival of animals under environmental challenges such as stress. However, the mechanisms through which dopaminergic transmission responds to stressful events and subsequently regulates its downstream neuronal activity during stress remain unknown. To investigate how dopamine signaling modulates stress-coping behavior, we measured the subsecond fluctuation of extracellular dopamine concentration and pH using fast scanning cyclic voltammetry (FSCV) in the NAc, a postsynaptic target of midbrain dopaminergic neurons, in male mice engaged in a tail suspension test (TST). The results revealed a transient decrease in dopamine concentration and an increase in pH levels when the animals changed behaviors...