Chronic musculoskeletal pain (CMP) is a significant burden for Persian Gulf War Veterans (GWVs), yet the causes are poorly understood. Brain structure abnormalities are observed in GWVs, however relationships with modifiable lifestyle factors such as physical activity (PA) are unknown. We evaluated gray matter volumes and associations with symptoms, PA, and sedentary time in GWVs with and without CMP. Ninety-eight GWVs (10 females) with CMP and 56 GWVs (7 females) controls completed T1-weighted magnetic resonance imaging, pain and fatigue symptom questionnaires, and PA measurement via actigraphy. Regional gray matter volumes were analyzed using voxel-based morphometry and were compared across groups using analysis of covariance (ANCOVA). Separate multiple linear regression models were used to test associations between PA intensities, sedentary time, symptoms, and gray matter volumes. Familywise cluster error rates were used to control for multiple comparisons (α = 0.05). GWVs with CMP reported greater pain...

Tao Yang, Macy W. Veling, Xiao-Feng Zhao, Nicholas P. Prin, Limei Zhu, et al. (see pages [5510–5521][1]) Down syndrome results from trisomy of chromosome 21. One of the genes present on this chromosome, Down syndrome cell adhesion molecule (DSCAM), has roles in dendritic arborization, dendritic

Brain enriched voltage-gated sodium channel (VGSC) Nav1.2 and Nav1.6 are critical for electrical signaling in the CNS. Previous studies have extensively characterized cell-type-specific expression and electrophysiological properties of these two VGSCs and how their differences contribute to fine-tuning of neuronal excitability. However, because of a lack of reliable labeling and imaging methods, the subcellular localization and dynamics of these homologous Nav1.2 and Nav1.6 channels remain understudied. To overcome this challenge, we combined genome editing, super-resolution, and live-cell single-molecule imaging to probe subcellular composition, relative abundances, and trafficking dynamics of Nav1.2 and Nav1.6 in cultured mouse and rat neurons and in male and female mouse brain. We discovered a previously uncharacterized trafficking pathway that targets Nav1.2 to the distal axon of unmyelinated neurons. This pathway uses distinct signals residing in the intracellular loop 1 between transmembrane domain I...

The subthalamic nucleus (STN) has been implicated in motor and nonmotor tasks, and is an effective target of deep brain stimulation for the treatment of Parkinson's disease, likely in part because of the STN's projections outside of the basal ganglia to other brain regions. While there is some evidence of a disynaptic connection between the STN and the cerebellum via the pontine nuclei (PN), how the STN modulates the activity of the neurons in the PN remains unknown. Here we addressed this question using a combination of anatomical tracings, optogenetics, and in vivo electrophysiology in both wild-type (WT) and transgenic mice of both sexes. Approximately half of recorded neurons in the PN, which were located primarily in the medial area, responded with short latency to both single pulses and trains of optogenetic stimulation of channelrhodopsin (ChR2)-expressing STN axons in awake, head-restrained mice. Furthermore, the increase in the activity of PN neurons correlated with the strength of activation of S...

The lateral habenula (LHb) balances reward and aversion by opposing activation of brain reward nuclei and is involved in the inhibition of responding for cocaine in a model of impulsive behavior. Previously, we reported that the suppression of cocaine seeking was prevented by LHb inactivation or nonselective antagonism of LHb mAChRs. Here, we investigate mAChR subtypes mediating the effects of endogenous acetylcholine in this model of impulsive drug seeking and define cellular mechanisms in which mAChRs alter LHb neuron activity. Using in vitro electrophysiology, we find that LHb neurons are depolarized or hyperpolarized by the cholinergic agonists oxotremorine-M (Oxo-M) and carbachol (CCh), and that mAChRs inhibit synaptic GABA and glutamatergic inputs to these cells similarly in male and female rats. Synaptic effects of CCh were blocked by the M2-mAChR (M2R) antagonist AFDX-116 and not by pirenzepine, an M1-mAChR (M1R) antagonist. Oxo-M-mediated depolarizing currents were also blocked by AFDX-116. Althou...

Deciding about courses of action involves minimizing costs and maximizing benefits. Decision neuroscience studies have implicated both the ventral and dorsal medial PFC (vmPFC and dmPFC) in signaling goal value and action cost, but the precise functional role of these regions is still a matter of debate. Here, we suggest a more general functional partition that applies not only to decisions but also to judgments about goal value (expected reward) and action cost (expected effort). In this conceptual framework, cognitive representations related to options (reward value and effort cost) are dissociated from metacognitive representations (confidence and deliberation) related to solving the task (providing a judgment or making a choice). We used an original approach aimed at identifying consistencies across several preference tasks, from likeability ratings to binary decisions involving both attribute integration and option comparison. fMRI results in human male and female participants confirmed the vmPFC as a...

Cerebral ischemia–reperfusion (I/R) injury in ischemic penumbra is accountable for poor outcome of ischemic stroke patients receiving recanalization therapy. Compelling evidence previously demonstrated a dual role of autophagy in stroke. This study aimed to understand the traits of autophagy in the ischemic penumbra and the potential mechanism that switches the dual role of autophagy. We found that autophagy induction by rapamycin and lithium carbonate performed before ischemia reduced neurologic deficits and infarction, while autophagy induction after reperfusion had the opposite effect in the male murine middle cerebral artery occlusion/reperfusion (MCAO/R) model, both of which were eliminated in mice lacking autophagy (Atg7flox/flox; Nestin-Cre). Autophagic flux determination showed that reperfusion led to a blockage of axonal autophagosome retrograde transport in neurons, which then led to autophagic flux damage. Then, we found that I/R induced changes in the protein levels of Sec22b and Ykt6 in neuron...

In the article “Improved Speech Hearing in Noise with Invasive Electrical Brain Stimulation,” by Prachi Patel, Bahar Khalijhinejad, Jose L. Herrero, Stephan Bickel, Ashesh D. Mehta, and Nima Mesgarani, which appeared on pages [3648–3658][1] of the April 27, 2022 issue, an author's name was

Neural adaptation enables the brain to efficiently process sensory signals despite large changes in background noise. Previous studies have established that recent background spectro- or spatio-temporal statistics scale neural responses to sensory stimuli via a canonical normalization computation, which is conserved among species and sensory domains. In the auditory pathway, one major form of normalization, termed contrast gain control, presents as decreasing instantaneous firing-rate gain, the slope of the neural input-output relationship, with increasing variability of background sound levels (contrast) across time and frequency. Despite this gain rescaling, mean firing-rates in auditory cortex become invariant to sound level contrast, termed contrast invariance. The underlying neuromodulatory mechanisms of these two phenomena remain unknown. To study these mechanisms in male and female mice, we used a 2-photon calcium imaging preparation in layer 2/3 neurons of primary auditory cortex (A1), along with p...