Highly correlated firing of primary afferent inputs and lamina I projection neurons evokes synaptic long-term potentiation (LTP), a mechanism by which ascending nociceptive transmission can be amplified at the level of the spinal dorsal horn. However, the degree to which neuromodulatory signaling shapes the temporal window governing spike-timing-dependent plasticity (STDP) at sensory synapses onto projection neurons remains unclear. The present study demonstrates that activation of spinal D1/D5 dopamine receptors (D1/D5Rs) creates a highly permissive environment for the production of LTP in male and female adult mouse spinoparabrachial neurons by promoting non-Hebbian plasticity. Bath application of the mixed D1/D5R agonist SKF82958 unmasked LTP at STDP pairing intervals that normally fail to alter synaptic efficacy. Furthermore, during D1/D5R signaling, action potential discharge in projection neurons became dispensable for LTP generation, and primary afferent stimulation alone was sufficient to induce st...

During neuronal migration, forces generated by cytoplasmic dynein yank on microtubules extending from the centrosome into the leading process and move the nucleus along microtubules that extend behind the centrosome. Scaffolds such as radial glia guide neuronal migration outward from the ventricles, but little is known about the internal machinery that ensures that the soma migrates along its proper path rather than moving backward or off the path. Here we report that depletion of KIFC1, a minus-end-directed kinesin called HSET in humans, causes neurons to migrate off their appropriate path, suggesting that this molecular motor is what ensures fidelity of the trajectory of migration. For these studies, we used rat migratory neurons in vitro and developing mouse brain in vivo , together with RNA interference and ectopic expression of mutant forms of KIFC1. We found that crosslinking of microtubules into a non-sliding mode by KIFC1 is necessary for dynein-driven forces to achieve sufficient traction to thrus...

Predicting and organizing patterns of events is important for humans to survive in a dynamically changing world. The motor system has been proposed to be actively, and necessarily, engaged in not only the production but the perception of rhythm by organizing hierarchical timing that influences auditory responses. It is not yet well understood how the motor system interacts with the auditory system to perceive and maintain hierarchical structure in time. This study investigated the dynamic interaction between auditory and motor functional sources during the perception and imagination of musical meters. We pursued this using a novel method combining high-density EEG, EMG, and motion capture with independent component analysis to separate motor and auditory activity during meter imagery while robustly controlling against covert movement. We demonstrated that endogenous brain activity in both auditory and motor functional sources reflects the imagination of binary and ternary meters in the absence of correspon...

JNeurosci is publishing an Expression of Concern for the article, “Reducing Amyloid-Related Alzheimer's Disease Pathogenesis by a Small Molecule Targeting Filamin A,” by Hoau-Yan Wang, Kalindi Bakshi, Maya Frankfurt, Andres Stucky, Marissa Goberdhan, Sanket M. Shah, and Lindsay H. Burns, which

Duloxetine, a serotonin and norepinephrine reuptake inhibitor, is the best-established treatment for painful chemotherapy-induced peripheral neuropathy (CIPN). While it is only effective in little more than half of patients, our ability to predict patient response remains incompletely understood. Given that stress exacerbates CIPN, and that the therapeutic effect of duloxetine is thought to be mediated, at least in part, via its effects on adrenergic mechanisms, we evaluated the contribution of neuroendocrine stress axes, sympathoadrenal and hypothalamic-pituitary-adrenal, to the effect of duloxetine in preclinical models of oxaliplatin- and paclitaxel-induced CIPN. Systemic administration of duloxetine, which alone had no effect on nociceptive threshold, both prevented and reversed mechanical hyperalgesia associated with oxaliplatin- and paclitaxel-CIPN. It more robustly attenuated oxaliplatin CIPN in male rats, while it was more effective for paclitaxel CIPN in females. Gonadectomy attenuated these sex d...

Sharp wave ripples (SW-Rs) in the hippocampus are synchronized bursts of hippocampal pyramidal neurons (PyNs), critical for spatial working memory. However, the molecular underpinnings of SW-Rs remain poorly understood. We show that SW-Rs in hippocampal slices from both male and female mice were suppressed by neuregulin 1 (NRG1), an epidermal growth factor whose expression is enhanced by neuronal activity. Pharmacological inhibition of ErbB4, a receptor tyrosine kinase for NRG1, increases SW-R occurrence rate in hippocampal slices. These results suggest an important role of NRG1-ErbB4 signaling in regulating SW-Rs. To further test this notion, we characterized SW-Rs in freely moving male mice, chemical genetic mutant mice, where ErbB4 can be specifically inhibited by the bulky inhibitor 1NMPP1. Remarkably, SW-R occurrence was increased by 1NMPP1. We found that 1NMPP1 increased the firing rate of PyN neurons, yet disrupted PyN neuron dynamics during SW-R events. Furthermore, 1NMPP1 increased SW-R occurrence...

JNeurosci is publishing an Expression of Concern for the article, “Dissociating β-Amyloid from α7 Nicotinic Acetylcholine Receptor by a Novel Therapeutic Agent, S 24795, Normalizes α7 Nicotinic Acetylcholine and NMDA Receptor Function in Alzheimer's Disease Brain,” by Hoau-Yan Wang, Andres

Multifaceted microglial functions in the developing brain, such as promoting the differentiation of neural progenitors and contributing to the positioning and survival of neurons, have been progressively revealed. Although previous studies have noted the relationship between vascular endothelial cells and microglia in the developing brain, little attention has been given to the importance of pericytes, the mural cells surrounding endothelial cells. In this study, we attempted to dissect the role of pericytes in microglial distribution and function in developing mouse brains. Our immunohistochemical analysis showed that approximately half of the microglia attached to capillaries in the cerebral walls. Notably, a magnified observation of the position of microglia, vascular endothelial cells and pericytes demonstrated that microglia were preferentially associated with pericytes that covered 79.8% of the total capillary surface area. Through in vivo pericyte depletion induced by the intraventricular administra...

Parkinson's disease (PD) is a neurodegenerative disease that includes motor impairments, such as tremor, bradykinesia, and postural instability. Although eye movement deficits are commonly found in saccade and pursuit tasks, preservation of oculomotor function has also been reported. Here we investigate specific task and stimulus conditions under which oculomotor function in PD is preserved. Sixteen PD patients and 18 healthy, age-matched controls completed a battery of movement tasks that included stationary or moving targets eliciting reactive or deliberate eye movements: pro-saccades, anti-saccades, visually guided pursuit, and rapid go/no-go manual interception. Compared with controls, patients demonstrated systematic impairments in tasks with stationary targets: pro-saccades were hypometric and anti-saccades were incorrectly initiated toward the cued target in ∼35% of trials compared with 14% errors in controls. In patients, task errors were linked to short latency saccades, indicating abnormalities i...