Activating transcription factor 4 [ATF4 (also called CREB2)], in addition to its well studied role in stress responses, is proposed to play important physiologic functions in regulating learning and memory. However, the nature of these functions has not been well defined and is subject to apparently disparate views. Here, we provide evidence that ATF4 is a regulator of excitability during synaptic plasticity. We evaluated the role of ATF4 in mature hippocampal cultures subjected to a brief chemically induced LTP (cLTP) protocol that results in changes in mEPSC properties and synaptic AMPA receptor density 1 h later, with return to baseline by 24 h. We find that ATF4 protein, but not its mRNA, is rapidly depleted by ∼50% in response to cLTP induction via NMDA receptor activation. Depletion is detectable in dendrites within 15 min and in cell bodies by 1 h, and returns to baseline by 8 h. Such changes correlate with a parallel depletion of phospho-eIF2a, suggesting that ATF4 loss is driven by decreased trans...

Neuron differentiation includes formation and outgrowth of neurites that differentiate into axons or dendrites. Directed neurite outgrowth is controlled by growth cones that protrude and retract actin-rich structures to sense environmental cues. These cues control local actin filament dynamics, steer growth cones toward attractants and away from repellents, and navigate neurites through the developing brain. Rodent hippocampal neurons are widely used to study the mechanisms underlying neuron differentiation. Genetic manipulation of isolated neurons including gene inactivation or reporter gene expression can be achieved by classical transfections methods, but these methods are restricted to neurons cultured for several days, after neurite formation or outgrowth. Instead, electroporation allows gene manipulation before seeding. However, reporter gene expression usually takes up to 24 h, and time course of gene inactivation depends on the half live of the targeted mRNA and gene product. Hence, these methods d...

Mutations of the gene encoding the RET tyrosine kinase causes Hirschsprung’s disease (HSCR) and medullary thyroid carcinoma (MTC). Current consensus holds that HSCR and MTC are induced by inactivating and activating RET mutations, respectively. However, it remains unknown whether activating mutations in the RET gene have adverse effects on ENS development in vivo . We addressed this issue by examining mice engineered to express RET51(C618F), an activating mutation identified in MTC patients. Although Ret51(C618F)/51(C618F) mice displayed hyperganglionosis of the ENS, Ret51(C618F)/- mice exhibited severe intestinal aganglionosis because of premature neuronal differentiation. Reduced levels of glial cell-derived neurotrophic factor (GDNF), a RET-activating neurotrophic factor, ameliorated the ENS phenotype of Ret51(C618F)/- mice, demonstrating that GDNF-mediated activation of RET51(C618F) is responsible for severe aganglionic phenotype. The RET51(C618F) allele showed genetic interaction with Ednrb gene, one ...

Parkinson’s disease (PD) is a progressive neurodegenerative disease that is typically diagnosed late in its progression. There is a need for biomarkers suitable for monitoring the disease progression at earlier stages to guide the development of novel neuroprotective therapies. One potential biomarker, α-synuclein, has been found in both the familial cases of PD, as well as the sporadic cases and is considered a key feature of PD. α-synuclein is naturally present in the retina, and it has been suggested that early symptoms of the visual system may be used as a biomarker for PD. Here, we use a viral vector to induce a unilateral expression of human wild-type α-synuclein in rats as a mechanistic model of protein aggregation in PD. We employed functional magnetic resonance imaging (fMRI) to investigate whether adeno-associated virus (AAV) mediated expression of human wild-type α-synuclein alter functional activity in the visual system. A total of 16 rats were injected with either AAV-α-synuclein ( n  = 7) or ...

Restoration of lost function following a nervous system injury is limited in adulthood as the regenerative capacity of nervous system declines with age. Pharmacological approaches have not been very successful in alleviating the consequences of nervous system injury. On the contrary, physical activity and rehabilitation interventions are often beneficial to improve the health conditions in the patients with neuronal injuries. Using touch neuron circuit of Caenorhabditis elegans , we investigated the role of physical exercise in the improvement of functional restoration after axotomy. We found that a swimming session of 90 min following the axotomy of posterior lateral microtubule (PLM) neuron can improve functional recovery in larval and adult stage animals. In older age, multiple exercise sessions were required to enhance the functional recovery. Genetic analysis of axon regeneration mutants showed that exercise-mediated enhancement of functional recovery depends on the ability of axon to regenerate. Exer...

Naltrexone is an opioid receptor antagonist approved for the treatment of alcohol and opioid use disorders at doses of 50–150 mg/d. Naltrexone has also been prescribed at much lower doses (3–6 mg/d) for the off-label treatment of inflammation and pain. Currently, a compelling mechanistic explanation for the reported efficacy of low-dose naltrexone (LDN) is lacking and none of the proposed mechanisms can explain patient reports of improved mood and sense of well-being. Here, we examined the possibility that LDN might alter the activity of the endogenous opioid system involving proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARH) in male and female mice. Known actions of POMC neurons could account for changes in pain perception and mood. However, using electrophysiologic, imaging and peptide measurement approaches, we found no evidence for such a mechanism. LDN did not change the sensitivity of opioid receptors regulating POMC neurons, the production of the β-endorphin precurso...

Environmental enrichment (EE) is beneficial to sensory functions. Thus, elucidating the neural mechanism underlying improvement of sensory stimulus discrimination is important for developing therapeutic strategies. We aim to advance the understanding of such neural mechanism. We found that tactile enrichment improved tactile stimulus feature discrimination. The neural correlate of such improvement was revealed by analyzing single-cell information coding in both the primary somatosensory cortex and the premotor cortex of awake behaving animals. Our results show that EE enhances the decision-information coding capacity of cells that are tuned to adjacent whiskers, and of premotor cortical cells.

Chronic vagus nerve stimulation (VNS) has been shown to facilitate learning, but effects of acute VNS on neural coding and behavior remain less well understood. Ferrets implanted with cuff electrodes on the vagus nerve were trained by classical conditioning on an auditory tone frequency-reward association. One tone was associated with reward while another tone was not. Tone frequencies and reward associations were changed every 2 d, requiring learning of a new relationship. When tones were paired with VNS, animals consistently learned the new association within 2 d. When VNS occurred randomly between trials, learning within 2 d was unreliable. In passively listening animals, neural activity in primary auditory cortex (A1) and pupil size were recorded before and after acute VNS-tone pairing. After pairing with a neuron’s best-frequency (BF) tone, responses by a subpopulation of neurons were reduced. VNS paired with an off-BF tone or during intertrial intervals had no effect. The BF-specific reduction in neu...

Neuropeptides are implicated in control of lateralized processes in the brain. A unilateral brain injury (UBI) causes the contralesional sensorimotor deficits. To examine whether opioid neuropeptides mediate UBI induced asymmetric processes we compared effects of opioid antagonists on the contralesional and ipsilesional hindlimb responses to the left-sided and right-sided injury in rats. UBI induced hindlimb postural asymmetry (HL-PA) with the contralesional hindlimb flexion, and activated contralesional withdrawal reflex of extensor digitorum longus (EDL) evoked by electrical stimulation and recorded with EMG technique. No effects on the interossei (Int) and peroneaus longus (PL) were evident. The general opioid antagonist naloxone blocked postural effects, did not change EDL asymmetry while uncovered cryptic asymmetry in the PL and Int reflexes induced by UBI. Thus, the spinal opioid system may either mediate or counteract the injury effects. Strikingly, effects of selective opioid antagonists were the i...

Synucleinopathies including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are characterized by neuronal intracellular inclusions of α-synuclein. PD dementia (PDD) and DLB are collectively the second most common cause of neurodegenerative dementia. In addition to associated inclusions, Lewy body diseases (LBDs) have dopaminergic neurodegeneration, motor defects and cognitive changes. The microtubule-associated protein tau has been implicated in LBDs, but the exact role of the protein and how it influences formation of α-synuclein inclusions is unknown. Reducing endogenous tau levels is protective in multiple models of Alzheimer’s disease (AD), tauopathies, and in some transgenic synucleinopathy mouse models. Recombinant α-synuclein and tau proteins interact in vitro . Here, we show tau and α-synuclein colocalize at excitatory presynaptic terminals. However, tau heterozygous and tau knock-out mice do not show a reduction in fibril-induced α-synuclein inclusions formation in primary cortical ne...