GABAB receptors in habenula cholinergic neurons mediate strong presynaptic excitation and control aversive memory expression. K+ channel tetramerization domain (KCTD) proteins are key interacting partners of GABAB receptors; it remains unclear whether and how KCTDs contribute to GABAB excitatory signaling. Here, we show that KCTD8 and KCTD12 in these neurons facilitate the GABAB receptors expression in axonal terminals and contribute to presynaptic excitation by GABAB receptors. Genetically knocking out KCTD8/12/16 , or KCTD8/12 , but not other combinations of the three KCTD isoforms, substantially reduced GABAB receptors–mediated potentiation of glutamate release and presynaptic Ca2+ entry in response to axonal stimulation, whereas they had no effect on GABAB-mediated inhibition in the somata of cholinergic neurons within the habenulo-interpeduncular pathway in mice of either sex. The physiological phenotypes were associated with a significant decrease in the GABAB expression within the axonal terminals b...

Humans rely on precise proprioceptive feedback from our muscles to perform daily activities, which is important in both the acquisition and execution of movements. Somatosensory input from the body shapes motor learning through central processes, as demonstrated for tasks using the arm, under active (self-generated) and passive conditions. Presently, we investigated whether passive movement training of the ankle increased proprioceptive acuity (psychophysical experiment) and whether it changed the peripheral proprioceptive afferent signal (microneurography experiment). In the psychophysical experiment, the ankle of 32 healthy human participants was moved passively using pairs of ramp-and-hold movements in different directions. In a pre-training test, participants made judgements about the movement direction in a two-alternative forced choice paradigm. Participants then underwent passive movement training, but only half were cued for learning, where a reference position was signaled by a sound and the parti...

Proper somatosensory circuit assembly is critical for processing somatosensory stimuli and for responding accordingly. In comparison to other sensory circuits (e.g., olfactory and visual), somatosensory circuits have unique anatomy and function. However, understanding of somatosensory circuit development lags far behind that of other sensory systems. For example, there are few identified transcription factors required for integration of interneurons into functional somatosensory circuits. Here, as a model, we examine one type of somatosensory interneuron, Even-skipped expressing Laterally placed interneurons (ELs) of the Drosophila larval nerve cord. Even-skipped (Eve) is a highly conserved, homeodomain transcription factor known to play a role in cell fate specification and neuronal axon guidance. Because marker genes are often functionally important in the cell types they define, we deleted eve specifically from EL interneurons. On the cell biological level, using single neuron labeling, we find eve play...

Oxytocin (Oxt) controls reproductive physiology and various kinds of social behaviors, but the exact contribution of Oxt to different components of parental care still needs to be determined. Here we illustrate the neuroanatomical relations of the parental nurturing-induced neuronal activation with magnocellular oxytocin neurons and fibers in the medial preoptic area (MPOA), the brain region critical for parental and alloparental behaviors. We utilized genetically-targeted mouse lines for Oxt , oxytocin receptor (Oxtr) , vasopressin receptor 1a (Avpr1a) , vasopressin receptor 1b (Avpr1b), and thyrotropin-releasing hormone (Trh) to systematically examine the role of Oxt-related signaling in pup-directed behaviors. The Oxtr - Avpr1a - Avpr1b triple knockout (TKO), and Oxt - Trh - Avpr1a - Avpr1b quadruple KO (QKO) mice were grossly healthy and fertile, except for their complete deficiency in milk ejection and modest deficiency in parturition secondary to maternal loss of the Oxt or Oxtr genes. In our minimal...

With increasing life span and prevalence of dementia, it is important to understand the mechanisms of cognitive aging. Here, we focus on a subgroup of the population we term “cognitively frail,” defined by reduced cognitive function in the absence of subjective memory complaints, or a clinical diagnosis of dementia. Cognitive frailty is distinct from cognitive impairment caused by physical frailty. It has been proposed to be a precursor to Alzheimer’s disease, but may alternatively represent one end of a nonpathologic spectrum of cognitive aging. We test these hypotheses in humans of both sexes, by comparing the structural and neurophysiological properties of a community-based cohort of cognitive frail adults, to people presenting clinically with diagnoses of Alzheimer’s disease or mild cognitive impairment, and community-based cognitively typical older adults. Cognitive performance of the cognitively frail was similar to those with mild cognitive impairment. We used a novel cross-modal paired-associates t...

Despite significant progress in understanding neural coding, it remains unclear how the coordinated activity of large populations of neurons relates to what an observer actually perceives. Since neurophysiological differences must underlie differences among percepts, differentiation analysis —quantifying distinct patterns of neurophysiological activity—has been proposed as an “inside-out” approach that addresses this question. This methodology contrasts with “outside-in” approaches such as feature tuning and decoding analyses, which are defined in terms of extrinsic experimental variables. Here we used two-photon calcium imaging in mice of both sexes to systematically survey stimulus-evoked neurophysiological differentiation in excitatory neuronal populations in layers 2/3, 4, and 5 across five visual cortical areas (primary, lateromedial, anterolateral, posteromedial, and anteromedial) in response to naturalistic and phase-scrambled movie stimuli. We find that unscrambled stimuli evoke greater neurophysio...

Episodic memory declines with advancing adult age. This decline is particularly pronounced when associations between items and their contexts need to be formed. According to theories of neural communication, the precise coupling of gamma power to the phase of the theta rhythm supports associative memory formation. To investigate whether age differences in associative memory are related to compromised theta–gamma coupling, we took EEG recordings during the encoding phase of an item-context association task. Fifty-eight younger (33 females) and 55 (24 females) older adults studied pictures of objects superimposed on background scenes. In a recognition test, objects were presented on old or new backgrounds, and participants responded if they had seen (1) the object and (2) the object–scene pair. Theta–gamma coupling supported pair memory formation in both age groups. Whereas pair memory was associated with coupling closer to the peak of the theta rhythm, item-only memory was associated with a deviation in pha...

The canonical view of motor control is that distal musculature is controlled primarily by the contralateral cerebral hemisphere; unilateral brain lesions typically affect contralateral but not ipsilateral musculature. Contralateral-only limb deficits following a unilateral lesion suggest but do not prove that control is strictly contralateral: the loss of a contribution of the lesioned hemisphere to the control of the ipsilesional limb could be masked by the intact contralateral drive from the non-lesioned hemisphere. To distinguish between these possibilities, we serially inactivated the parietal reach region (PRR), comprising the posterior portion of medial intraparietal area (MIP), the anterior portion of V6a and portions of the lateral occipital parietal area (LOP), in each hemisphere of two monkeys (23 experimental sessions, 46 injections total) to evaluate PRR’s contribution to the contralateral reaching deficits observed following lateralized brain lesions. Following unilateral inactivation, reach r...

Synaptic vesicle (SV) recycling is essential for the maintenance of neurotransmission, with a number of neurodevelopmental disorders linked to defects in this process. Fragile X syndrome (FXS) results from a loss of fragile X mental retardation protein (FMRP) encoded by the FMR1 gene. Hyperexcitability of neuronal circuits is a key feature of FXS, therefore we investigated whether SV recycling was affected by the absence of FMRP during increased neuronal activity. We revealed that primary neuronal cultures from male Fmr1 knockout rats display a specific defect in activity-dependent bulk endocytosis (ADBE). ADBE is dominant during intense neuronal activity, and this defect resulted in an inability of Fmr1 knockout neurons to sustain SV recycling during trains of high frequency stimulation. Using a molecular replacement strategy, we also revealed that a human FMRP mutant that cannot bind BK channels failed to correct ADBE dysfunction in knockout neurons, however this dysfunction was corrected by BK channel a...

Spinal cord injury (SCI) is a devastating condition. Splenectomy may play a protective role in the development of SCI. However, little is known about whether the timing of splenectomy affects the outcome after SCI. Investigation into splenectomy after SCI would provide insight into how the timing can be selected following SCI to improve neurological outcomes. Rats were randomized into a sham group, a nonsplenectomized group (NonSPX), four splenectomized groups with the surgery performed immediately, 6 h, 12 h, and 24 h after SCI (SPX0, SPX6, SPX12, and SPX24, respectively). Rats were subjected to severe contusive SCI at the level of the third thoracic vertebra. At different time points following SCI, BBB score was used to assess the recovery of injury. The animals in each group were randomly selected for tissue collection at day 3, 14, and 28 after surgery. Then, immunohistochemistry of immunologic cells was performed and inflammatory mediators were determined. Our study showed that splenectomy within 6 h ...