Motor adaptation is crucial for performing accurate movements in a changing environment and relies on the cerebellum. Although cerebellar involvement has been well characterized, the neurochemical changes in the cerebellum underpinning human motor adaptation remain unknown. We used a novel magnetic resonance spectroscopic imaging (MRSI) technique to measure changes in the inhibitory neurotransmitter GABA in the human cerebellum during visuomotor adaptation. Participants ( n = 17, six female) used their right hand to adapt to a rotated cursor in the scanner, compared with a control task requiring no adaptation. We spatially resolved adaptation-driven GABA changes at the cerebellar nuclei and cerebellar cortex in the left and the right cerebellar hemisphere independently and found that simple right-hand movements increase GABA in the right cerebellar nuclei and decreases GABA in the left. When isolating adaptation-driven GABA changes, we found that GABA in the left cerebellar nuclei and the right cerebellar ...

Forelimb-related areas of the motor cortex communicate directly to downstream areas in the brainstem and spinal cord via axons that project to and through the pyramidal tract (PT). To better understand the diversity of the brainstem branching patterns of these pyramidal tract projections, we used MAPseq, a molecular barcode technique for population-scale sampling with single-axon resolution. In experiments using mice of both sexes, we first confirmed prior results demonstrating the basic efficacy of axonal barcode identification of primary motor cortex (M1) PT-type axons, including corticobulbar (CBULB) and corticospinal (CSPI) subclasses. We then used multiplexed MAPseq to analyze projections from M1 and M2 (caudal and rostral forelimb areas). The four basic axon subclasses comprising these projections (M1-CSPI, M1-CBULB, M2-CSPI, M2-CBULB) showed a complex mix of differences and similarities in their brainstem projection profiles. This included relatively abundant branching by all classes in the dorsal m...

The midbrain periaqueductal gray (PAG) plays a central role in pain modulation via descending pathways. Opioids and cannabinoids are thought to activate these descending pathways by relieving intrinsic GABAergic inhibition of PAG neurons which project to the rostroventromedial medulla (RVM), a process known as disinhibition. However, the PAG also receives descending extrinsic GABAergic inputs from the central nucleus of the amygdala (CeA) which are thought to inhibit PAG GABAergic interneurons. It remains unclear how opioids and cannabinoids act at these different synapses to control descending analgesic pathways. We used optogenetics, tract tracing and electrophysiology to identify the circuitry underlying opioid and cannabinoid actions within the PAG of male and female rats. It was observed that both RVM-projection and nonprojection PAG neurons received intrinsic-PAG and extrinsic-CeA synaptic inputs, which were predominantly GABAergic. Opioids acted via presynaptic µ-receptors to suppress both intrinsic...

Autism is characterized by two key diagnostic criteria including social deficits and repetitive behaviors. Although recent studies implicated ventral striatum in social deficits and dorsal striatum in repetitive behaviors, here we revealed coexisting and opposite morphologic and functional alterations in the dorsostriatal direct and indirect pathways, and such alterations in these two pathways were found to be responsible, respectively, for the two abovementioned different autism-like behaviors exhibited by male mice prenatally exposed to valproate. The alteration in direct pathway was characterized by a potentiated state of basal activity, with impairment in transient responsiveness of D1-MSNs during social exploration. Concurrent alteration in indirect pathway was a depressed state of basal activity, with enhancement in transient responsiveness of D2-MSNs during repetitive behaviors. A causal relationship linking such differential alterations in these two pathways to the coexistence of these two autism-l...

Jing-Jing Liu, Katherine W. Eyring, Gabriele M. König, Evi Kostenis, and Richard W. Tsien (see pages [7707–7720][1]) Interest in hippocampal area CA2 has grown substantially since the area was discovered to have essential roles in social interaction. In particular, blocking output from dorsal

To ensure survival in a dynamic environment, the human neocortex monitors input streams from different sensory organs for important sensory events. Which principles govern whether different senses share common or modality-specific brain networks for sensory target detection? We examined whether complex targets evoke sustained supramodal activity while simple targets rely on modality-specific networks with short-lived supramodal contributions. In a series of hierarchical multisensory target detection studies (n=77, of either sex) using Electroencephalography, we applied a temporal cross-decoding approach to dissociate supramodal and modality-specific cortical dynamics elicited by rule-based global and feature-based local sensory deviations within and between the visual, somatosensory and auditory modality. Our data show that each sense implements a cortical hierarchy orchestrating supramodal target detection responses which operate at local and global timescales in successive processing stages. Across diffe...

In recent years research on natural speech processing has benefited from recognizing that low-frequency cortical activity tracks the amplitude envelope of natural speech. However, it remains unclear to what extent this tracking reflects speech-specific processing beyond the analysis of the stimulus acoustics. In the present study, we aimed to disentangle contributions to cortical envelope tracking that reflect general acoustic processing from those that are functionally related to processing speech. To do so, we recorded EEG from subjects as they listened to auditory chimeras, stimuli composed of the temporal fine structure of one speech stimulus modulated by the amplitude envelope (ENV) of another speech stimulus. By varying the number of frequency bands used in making the chimeras, we obtained some control over which speech stimulus was recognized by the listener. No matter which stimulus was recognized, envelope tracking was always strongest for the ENV stimulus, indicating a dominant contribution from ...

Midfrontal theta (FMθ) in the human EEG is commonly viewed as a generic and homogeneous mechanism of cognitive control in general and conflict processing in particular. However, the role of FMθ in approach–avoidance conflicts and its cross-task relationship to simpler stimulus-response conflicts remain to be examined more closely. Therefore, we recorded EEG data while 59 healthy participants (49 female, 10 male) completed both an approach–avoidance task and a flanker task. Participants showed significant increases in FMθ power in response to conflicts in both tasks. To our knowledge, this is the first study to show a direct relationship between FMθ and approach–avoidance conflicts. Crucially, FMθ activity was task dependent and showed no cross-task correlation. To assess the possibility of multiple FMθ sources, we applied source separation [generalized eigendecomposition (GED)] to distinguish independent FMθ generators. The activity of the components showed a similar pattern and was again task specific. Ho...

The perception of dynamic visual stimuli relies on two apparently conflicting perceptual mechanisms: rapid visual input must sometimes be integrated into unitary percepts but at other times must be segregated or parsed into separate objects or events. Though they have opposite effects on our perceptual experience, the deployment of spatial attention benefits both operations. Little is known about the neural mechanisms underlying this impact of spatial attention on temporal perception. Here, we record magnetoencephalography (MEG) in male and female humans to demonstrate that the deployment of spatial attention for the purpose of segregating or integrating visual stimuli impacts prestimulus oscillatory activity in retinotopic visual brain areas where the attended location is represented. Alpha band oscillations contralateral to an attended location are therefore faster than ipsilateral oscillations when stimuli appearing at this location will need to be segregated, but slower in expectation of the need for i...

The pathophysiological features of ischemia-related blood-brain barrier (BBB) disruption are widely studied using preclinical stroke models. However, in many of these models, craniectomy is required to confirm arterial occlusion via laser Doppler flowmetry or to enable direct ligation of the cerebral artery. In the present study, mice were used to construct a distal middle cerebral artery occlusion (dMCAO) model, a preclinical stroke model that requires craniectomy to enable direct ligation of the cerebral artery, or subjected to craniectomy alone. dMCAO but not craniectomy caused neurodegeneration and cerebral infarction, but both procedures induced an appreciable increase in BBB permeability to Evans blue dye (EBD), fluorescein, and endogenous albumin but not to 10 kD dextran-FITC, leading to cerebral edema. Using rats, we further showed that BBB disruption induced by craniectomy with no evidence of dural tearing was comparable to that induced by craniectomy involving tearing of the dura. In conclusion, ...