The development of the human brain continues through to early adulthood. It has been suggested that cortical plasticity during this protracted period of development shapes circuits in associative transmodal regions of the brain. Here we considered how cortical plasticity during development might contribute to the coordinated brain activity required for speech motor learning. Specifically, we examined patterns of brain functional connectivity whose strength covaried with the capacity for speech audio-motor adaptation in children ages 5–12 and in young adults of both sexes. Children and adults showed distinct patterns of the encoding of learning in the brain. Adult performance was associated with connectivity in transmodal regions that integrate auditory and somatosensory information, whereas children rely on basic somatosensory and motor circuits. A progressive reliance on transmodal regions is consistent with human cortical development and suggests that human speech motor adaptation abilities are built on ...

Neural dynamics in response to affective stimuli are linked to momentary emotional experiences. The amygdala, in particular, is involved in subjective emotional experience and assigning value to neutral stimuli. Because amygdala activity persistence following aversive events varies across individuals, some may more readily evaluate subsequent neutral stimuli than others. This may lead to more frequent and long-lasting momentary emotional experiences, which may also be linked to self-evaluative measures of psychological well-being (PWB). Despite extant links between daily affect and PWB, few studies have directly explored the links between amygdala persistence, daily affective experience, and PWB. To that end, we examined data from 52 human adults (67% female) in the Midlife in the United States (MIDUS) study who completed measures of PWB, daily affect, and functional MRI (fMRI). During fMRI, participants viewed affective images followed by a neutral facial expression, permitting quantification of individua...

Understanding how and where in the brain sentence-level meaning is constructed from words presents a major scientific challenge. Recent advances have begun to explain brain activation elicited by sentences using vector models of word meaning derived from patterns of word co-occurrence in text corpora. These studies have helped map out semantic representation across a distributed brain network spanning temporal, parietal and frontal cortex. However, it remains unclear whether activation patterns within regions reflect unified representations of sentence-level meaning, as opposed to superpositions of context-independent component words. This is because models have typically represented sentences as “bags-of-words” that neglect sentence-level structure. To address this issue, we interrogated fMRI activation elicited as 240 sentences were read by 14 participants (9F, 5M), using sentences encoded by a recurrent deep artificial neural-network trained on a sentence inference task (InferSent). Recurrent connection...

Although cocaine is powerfully rewarding, not all individuals are equally prone to abusing this drug. We postulate that these differences arise in part because some individuals exhibit stronger aversive responses to cocaine that protect against cocaine seeking. Indeed, using conditioned place preference (CPP) and a runway operant cocaine self-administration task, we demonstrate that avoidance responses to cocaine vary greatly between individual "high cocaine-avoider" and "low cocaine-avoider" rats. These behavioral differences correlated with cocaine-induced activation of the RMTg, measured using both in vivo firing and cFos, while slice electrophysiological recordings from VTA-projecting RMTg neurons showed that, relative to low-avoiders, high-avoiders exhibited greater intrinsic excitability, greater transmission via calcium-permeable AMPA receptors (CP-AMPARs), and higher presynaptic glutamate release. In behaving animals, blocking CP-AMPARs in the RMTg with NASPM reduced cocaine avoidance. Hence, cocai...

Demand theory can be applied to analyze how animal consumers change their selection of commodities in response to changes in commodity prices, given budget constraints. Previous work has shown that demand elasticities in rats differed between uncompensated budget conditions in which the budget available to be spent on the commodities (e.g., the finite number of discrete operants to ‘purchase’ rewards in two-alternative fixed-ratio schedules) was kept constant, and compensated budget conditions in which the budget was adjusted so that consumers could potentially continue to obtain the original reward bundles. Here, we hypothesized that rat anterior cingulate cortex (ACC) was necessary to produce this budget effect on demand elasticities. We applied excitotoxic or sham lesions to ACC in rats performing an effort task in which the prices of liquid vanilla or chocolate rewards (the effort required to obtain rewards) and the budget (the total number of operants) was manipulated. When reward prices changed, and ...

Diabetic neuropathic pain (DNP) is a common complication of diabetes characterized by persistent pain. Emerging evidence links astrocytes to mechanical nociceptive processing, and the motor cortex (MCx) is a cerebral cortex region that is known to play a key role in pain regulation. However, the association between MCx astrocytes and DNP pathogenesis remains largely unexplored. Here, we studied this association using designer receptors exclusively activated by designer drugs (DREADDs) to specifically manipulate MCx astrocytes. We proved that the selective inhibition of MCx astrocytes reduced DNP in streptozocin (STZ)-induced DNP models and discovered a potential mechanism by which astrocytes release cytokines, including tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β), to increase neuronal activation in the MCx, thereby regulating pain. Together, these results demonstrate a pivotal role for MCx astrocytes in DNP pathogenesis and provide new insight into DNP treatment strategies. Signific...

Sleep has been shown to be critical for memory consolidation, with some research suggesting that certain memories are prioritized for consolidation. Initial strength of a memory appears to be an important boundary condition in determining which memories are consolidated during sleep. However, the role of consolidation-mediating oscillations, such as sleep spindles and slow oscillations, in this preferential consolidation has not been explored. Here, 54 human participants (76% female) studied pairs of words to three distinct encoding strengths, with recall being tested immediately following learning and again six hours later. Thirty-six had a two-hour nap opportunity following learning, whilst the remaining 18 remained awake throughout. Results showed that across six hours awake, weakly encoded memories deteriorated the fastest. In the nap group however, this effect was attenuated, with forgetting rates equivalent across encoding strengths. Within the nap group, consolidation of weakly encoded items was ass...

The Abelson-helper integration site 1 ( AHI1 ) gene encodes for a ciliary transition zone localizing protein that when mutated causes the human ciliopathy, Joubert syndrome. We prepared and examined neuronal cultures derived from male and female embryonic Ahi1 +/+ and Ahi1 -/- mice (littermates) and found that the distribution of ciliary MchR1 was significantly reduced in Ahi1 -/- neurons; however, the total and surface expression of MchR1 on Ahi1 -/- neurons was similar to controls ( Ahi1 +/+). This indicates that a pathway for MchR1 trafficking to the surface plasma membrane is intact, but the process of targeting MchR1 into cilia is impaired in Ahi1 deficient mouse neurons, indicating a role for Ahi1 in localizing MchR1 to the cilium. Mouse Ahi1 -/- neurons that fail to accumulate MchR1 in the ciliary membrane have significant decreases in two downstream MchR1 signaling pathways (cAMP and Erk) upon MCH stimulation. These results suggest that the ciliary localization of MchR1 is necessary and critical fo...

Dopaminergic (DA) neurons of the midbrain are involved in controlling animals’ orienting and approach toward relevant external stimuli. The firing of DA neurons is regulated by many brain structures; however, the sensory input is provided predominantly by the ipsilateral superior colliculus (SC). It is suggested that SC also innervates the contralateral rostromedial tegmental nucleus (RMTg)—the main inhibitory input to DA neurons. Therefore, this study aimed to describe the physiology and anatomy of the SC-RMTg pathway. To investigate the anatomical connections within the circuit of interest, anterograde, retrograde, and transsynaptic tract-tracing studies were performed on male Sprague-Dawley rats. We have observed that RMTg is monosynaptically innervated predominantly by the lateral parts of the intermediate layer of the contralateral SC. To study the physiology of this neuronal pathway, we conducted in vivo electrophysiological experiments combined with optogenetics; the activity of RMTg neurons was rec...

The release of small extracellular vesicles (sEV) has recently been reported, but knowledge of their function in neuron development remains limited. Using LC-MS/MS, we found that sEVs released from developing cortical neurons in vitro obtained from mice of both sexes were enriched in cytoplasm, exosome, and protein- and DNA/RNA-binding pathways. The latter included HDAC2, which was of particular interest because HDAC2 regulates spine development and populations of neurons expressing different levels of HDAC2 co-exist in vivo during the period of spine growth. Here, we found that HDAC2 levels decrease in neurons as they acquire synapses, and that sEVs from HDAC2-rich neurons regulate HDAC2 signaling in HDAC2-low neurons possibly through HDAC2 transfer. This regulation led to a transcriptional decrease in HDAC2 synaptic targets and the density of excitatory synapses. These data suggest that sEVs provide inductive cell-cell signaling that coordinates the development of dendritic spines via the activation of H...