Midbrain dopamine neurons play central physiological roles in voluntary movement, reward learning, and motivated behavior. Inhibitory signaling at somatodendritic dopamine D2 receptor (D2R) synapses modulates excitability of dopamine neurons. The neuropeptide neurotensin is expressed by many inputs to the midbrain and induces LTD of D2R synaptic currents (LTDDA); however, the source of neurotensin that is responsible for LTDDA is not known. Here we show, in brain slices from male and female mice, that LTDDA is driven by neurotensin released by dopamine neurons themselves. Optogenetic stimulation of dopamine neurons was sufficient to induce LTDDA in the substantia nigra, but not the VTA, and was dependent on neurotensin receptor signaling, postsynaptic calcium, and vacuolar-type H+-ATPase activity in the postsynaptic cell. These findings reveal a novel form of signaling between dopamine neurons involving release of the peptide neurotensin, which may act as a feedforward mechanism to increase dopamine neuron...

As humans are social beings, human behavior and cognition are fundamentally shaped by information provided by peers, making human subjective value for rewards prone to be manipulated by perceived social information. Even subtle nonverbal social information, such as others' eye gazes, can influence value assignment, such as food value. In this study, we investigate the neural underpinnings of how gaze cues modify participants' food value (both genders) by means of functional magnetic resonance imaging. During the gaze-cuing task, food items were repeatedly presented either while others looked at them or while they were ignored by others. We determined participants' food values by assessing their willingness to pay before and after a standard gaze-cuing training. Results revealed that participants were willing to pay significantly more for food items that were attended to by others compared with the unattended to food items. Neural data showed that differences in subjective values between the two conditions ...

T-Box Brain Transcription Factor 1 (TBR1) plays essential roles in brain development, mediating neuronal migration, fate specification, and axon tract formation. While heterozygous loss-of-function and missense TBR1 mutations are associated with neurodevelopmental conditions, the effects of these heterogeneous mutations on brain development have yet to be fully explored. We characterized multiple mouse lines carrying Tbr1 mutations differing by type and exonic location, including the previously generated Tbr1 exon 2–3 knockout (KO) line, and we analyzed male and female mice at neonatal and adult stages. The frameshift patient mutation A136PfsX80 (A136fs) caused reduced TBR1 protein in cortex similar to Tbr1 KO, while the missense patient mutation K228E caused significant TBR1 upregulation. Analysis of cortical layer formation found similar defects between KO and A136fs homozygotes in their CUX1+ and CTIP2+ layer positions, while K228E homozygosity produced layering defects distinct from these mutants. Mean...

Drosophila Multiple Epidermal Growth Factor-like Domains 8 (dMegf8) is a homolog of human MEGF8. MEGF8 encodes a multi-domain transmembrane protein which is highly conserved across species. In humans, MEGF8 mutations cause a rare genetic disorder called Carpenter syndrome, which is frequently associated with abnormal left-right patterning, cardiac defects and learning disabilities. MEGF8 is also associated with psychiatric disorders. Despite its clinical relevance MEGF8 remains poorly characterized, and though it is highly conserved, studies on animal models of Megf8 are also very limited. The presence of intellectual disabilities in Carpenter syndrome patients and association of MEGF8 with psychiatric disorders indicate that mutations in MEGF8 cause underlying defects in synaptic structure and functions. In this study, we investigated the role of Drosophila dMegf8 in glutamatergic synapses of the larval neuromuscular junctions (NMJ) in both males and females. We show that dMegf8 localizes to NMJ synapses ...

Conversion of astroglia into functional neurons has been considered as a promising therapeutic strategy for neurodegenerative diseases. Recent studies reported that downregulation of the RNA binding protein, PTBP1, converts astrocytes into neurons in situ in multiple mouse brain regions, consequently improving pathological phenotypes associated with Parkinson’s disease, RGC loss, and aging. Here, we demonstrate that PTBP1 downregulation using an astrocyte specific AAV-mediated shRNA system fails to convert hippocampal astrocytes into neurons in both male and female WT, and β-amyloid (5×FAD) and tau (PS19) Alzheimer’s disease (AD) mouse models, and fails to reverse synaptic/cognitive deficits and AD-associated pathology in male mice. Similarly, PTBP1 downregulation cannot convert astrocytes into neurons in the striatum and substantia nigra in both male and female WT mice. Together, our study suggests that cell fate conversion strategy for neurodegenerative disease therapy through manipulating one single gen...

Neuroimaging, neuropsychological, and psychophysical evidence indicates that concept retrieval selectively engages specific sensory and motor brain systems involved in the acquisition of the retrieved concept. However, it remains unclear which supramodal cortical regions contribute to this process and what kind of information they represent. Here, we used representational similarity analysis of two large fMRI data sets, with a searchlight approach, to generate a detailed map of human brain regions where the semantic similarity structure across individual lexical concepts can be reliably detected. We hypothesized that heteromodal cortical areas typically associated with the “default mode network” encode multimodal experiential information about concepts, consistent with their proposed role as cortical integration hubs. In two studies involving different sets of concepts and different participants (both sexes), we found a distributed, bihemispheric network engaged in concept representation, composed of high-...

The primary sensory modality for probing spatial orientation can vary among psychophysical tasks. In the subjective visual vertical (SVV) task, a visual stimulus is used to measure perceived vertical orientation while a haptic stimulus is used in the subjective haptic vertical (SHV) task. Here we examined disparity in SHV and SVV results and asked whether it could be related to biases in probing different spatial estimates by each task. Forty-two healthy volunteers (25 ± 10 years [Mean ± SD]; 19 female; 21 left-handed) were recruited. The effect of task to measure spatial orientation was calculated as the difference between SHV and SVV values, and with the head upright and tilted 20° laterally. There was a task bias irrespective of head position related to hand use in the haptic task but not handedness (left hand -3.7 ± 1.1° [Mean head upright ± SEM]; right hand 7.9 ± 1.0°). When this task bias was subtracted out, there was a similar spatial bias using each hand in SHV task that was also comparable with th...

Objectives: Multiple sclerosis (MS) is a progressive and inflammatory demyelinating disease of the central nervous system (CNS). Peroxisomes perform critical functions that contribute to CNS homeostasis. We investigated peroxisome injury and mitigating effects of peroxisome-restorative therapy on inflammatory demyelination in models of MS. Methods: Human autopsied CNS tissues (male and female), human cell cultures and cuprizone-mediated demyelination mice (female) were examined by RT-PCR, western blotting and immunolabeling. The therapeutic peroxisome proliferator, 4-phenylbutyrate (4-PBA) was investigated in vitro and in vivo. Results: White matter from MS patients showed reduced peroxisomal transcript and protein levels, including PMP70, compared to non-MS controls. Cultured human neural cells revealed that human microglia contained abundant peroxisomal proteins. TNF-α-exposed microglia displayed reduced immunolabeling of peroxisomal proteins, PMP70 and PEX11β, which was prevented with 4-PBA. In human ...

How do we come to sense that a hand in view belongs to our own body or not? Previous studies have suggested that the integration of vision and somatosensation in the frontoparietal areas plays a critical role in the sense of body ownership, i.e., the multisensory perception of limbs and body parts as our own. However, little is known about how these areas implement the multisensory integration process at the computational level and whether activity predicts illusion elicitation in individual participants on a trial-by-trial basis. To address these questions, we used functional magnetic resonance imaging and a rubber hand illusion-detection task and fitted the registered neural responses to a Bayesian causal inference model of body ownership. Thirty healthy human participants (male and female) performed 12-second trials with varying degrees of asynchronously delivered visual and tactile stimuli of a rubber hand (in view) and a (hidden) real hand. After the 12-second period, participants had to judge whether...

In severely affected stroke survivors, cortico-muscular control is disturbed and volitional upper limb movements often absent. Mental rehearsal of the impaired movement in conjunction with sensory feedback provision are suggested as promising rehabilitation exercises. Knowledge about the underlying neural processes, however, remains vague. In male and female chronic stroke patients with hand paralysis, a brain-computer interface controlled a robotic orthosis and turned sensorimotor beta-band desynchronization during motor imagery (MI) of finger extension into contingent hand opening. Healthy control subjects performed the same task and received the same proprioceptive feedback with a robotic orthosis or visual feedback only. Only when proprioceptive feedback was provided, cortico-muscular coherence (CMC) increased with a predominant information flow from the sensorimotor cortex to the finger extensors. This effect (i) was specific to the beta frequency-band, (ii) transferred to a motor task, (iii) was prop...