Zimmermannashby1420

The consequence of repeated cocaine exposure and prolonged abstinence on glutamate receptor expression in the nucleus accumbens has been extensively studied. However, the early effects of cocaine on NMDAR signaling remain unknown. NMDAR signaling depends on the subunit composition, subcellular localization, and the interaction with proteins at the postsynaptic density (PSD), where NMDARs and other proteins form supercomplexes that are responsible for the signaling pathways activated by NMDAR-induced Ca2+ influx. Here, we investigated the effect of cocaine on NMDAR subunit composition and subcellular localization after both intraperitoneal non-contingent cocaine and response-contingent intravenous cocaine self-administration in mice. We found that repeated cocaine exposure, regardless of the route or contingency of drug administration, decreases NMDAR interactions with the PSD and synaptic lipid rafts in the accumbens shell and dorsal striatum. We provide evidence that cocaine triggers an early redistribution of NMDARs from synaptic to extrasynaptic sites, and that this adaptation has implications in the activation of downstream signaling pathways. Thus, consistent with a loss of NMDAR function, cocaine-induced ERK phosphorylation is attenuated. Because early NMDAR activity contributes to the initiation of lasting addiction-relevant neuroadaptations, these data may hold clues into cellular mechanisms responsible for the development of cocaine addiction.

Attention and perception are strongly biased toward information about oneself compared to information about others. The self-attention network, an integrative theoretical framework for understanding the self-prioritization effects (SPE), proposes that the ventromedial prefrontal cortex (VMPFC), and the posterior superior temporal sulcus (pSTS) are the two nodes responsible for the preferential processing of self-related stimuli, which interact with the attentional control network (associated with the dorsolateral prefrontal cortex, DLPFC), responsible for processing other-related stimuli. So far, neuroimaging studies have provided considerable correlational evidence supporting the self-attention network.

Here we went beyond correlational evidence by manipulating cortical activity using high-definition transcranial direct current stimulation (HD-tDCS), a non-invasive brain stimulation method. We assessed whether anodal and cathodal stimulation of the VMPFC or the DLPFC modulates the processing of self- andPFC/DLPFC and the impact of personal significance stimuli on perception.

We discuss the implications of these findings, in particular why cognitive modeling theories about SPEs should favor an epiphenomenal rather than a causal link between VMPFC/DLPFC and the impact of personal significance stimuli on perception.Diabetes mellitus (DM) and Parkinson's disease (PD) have been and will continue to be two common chronic diseases globally that are difficult to diagnose during the prodromal phase. Current molecular genetics, cell biological, and epidemiological evidences have shown the correlation between PD and DM. PD shares the same pathogenesis pathways and pathological factors with DM. In addition, β-cell reduction, which can cause hyperglycemia, is a striking feature of DM. Recent studies indicated that hyperglycemia is highly relevant to the pathologic changes in PD. However, further correlation between DM and PD remains to be investigated. Intriguingly, polycystic monoamine transporter 2 (VMAT2), which is co-expressed in dopaminergic neurons and β cells, is responsible for taking up dopamine into the presynaptic vesicles and can specifically bind to the β cells. #link# Furthermore, we have summarized the specific molecular and diagnostic functions of VMAT2 for the two diseases reported in this review. Therefore, VMAT2 can be applied as a target probe for positron emission tomography (PET) imaging to detect β-cell and dopamine level changes, which can contribute to the diagnosis of DM and PD during the prodromal phase. Targeting VMAT2 with the molecular probe 18F-FP-(+)-DTBZ can be an entry point for the β cell mass (BCM) changes in DM at the molecular level, to clarify the potential relationship between DM and PD. VMAT2 has promising clinical significance in investigating the pathogenesis, early diagnosis, and treatment evaluation of the two diseases.Amyotrophic lateral sclerosis (ALS) is a progressive and devastating multifactorial neurodegenerative disorder. Although the pathogenesis of ALS is still not completely understood, numerous studies suggest that mitochondrial deregulation may be implicated in its onset and progression. Interestingly, mitochondrial deregulation has also been associated with changes in neural stem cells (NSC) proliferation, differentiation, and migration. In this review, we highlight the importance of mitochondrial function for neurogenesis, and how both processes are correlated and may contribute to the pathogenesis of ALS; we have focused primarily on preclinical data from animal models of ALS, since to date no studies have evaluated this link using human samples. As there is currently no cure and no effective therapy to counteract ALS, we have also discussed how improving neurogenic function by epigenetic modulation could benefit ALS. In support of this hypothesis, changes in histone deacetylation can alter mitochondrial function, which in turn might ameliorate cellular proliferation as well as neuronal differentiation and migration. We propose that modulation of epigenetics, mitochondrial function, and neurogenesis might provide new hope for ALS patients, and studies exploring these new territories are warranted in the near future.A long-standing goal of translational neuroscience is the ability to noninvasively deliver therapeutic agents to specific brain regions with high spatiotemporal resolution. Focused ultrasound (FUS) is an emerging technology that can noninvasively deliver energy up the order of 1 kW/cm2 with millimeter and millisecond resolution to any point in the human brain with Food and Drug Administration-approved hardware. Although FUS is clinically utilized primarily for focal ablation in conditions such as essential tremor, recent breakthroughs have enabled the use of FUS for drug delivery at lower intensities (i.e., tens of watts per square centimeter) without ablation of the tissue. In this review, we present strategies for image-guided FUS-mediated pharmacologic neurointerventions. First, we discuss blood-brain barrier opening to deliver therapeutic agents of a variety of sizes to the central nervous system. We then describe the use of ultrasound-sensitive nanoparticles to noninvasively deliver small molecules to millimeter-sized structures including superficial cortical regions and deep gray matter regions within the brain without the need for blood-brain barrier opening. We also consider the safety and potential complications of these techniques, with attention to temporal acuity. Finally, we close with a discussion of different methods for mapping the ultrasound field within the brain and describe future avenues of research in ultrasound-targeted drug therapies.Neural tube defects (NTDs) are severe malformations of the central nervous system that affect 1-2 individuals per 2,000 births. Their etiology is complex and involves both genetic and environmental factors. Our recent discovery that simultaneous removal of Cldn3, -4, and -8 from tight junctions results in cranial and spinal NTDs in both chick and mouse embryos suggests that claudins play a conserved role in neural tube closure in vertebrates. To determine if claudins were associated with NTDs in humans, we used a Fluidigm next generation sequencing approach to identify genetic variants in CLDN loci in 152 patients with spinal NTDs. We identified eleven rare and four novel missense mutations in ten CLDN genes. In vivo validation of variant pathogenicity using a chick embryo model system revealed that overexpression of four variants caused a significant increase in NTDs CLDN3 A128T, CLDN8 P216L, CLDN19 I22T, and E209G. Our data implicate rare missense variants in CLDN genes as risk factors for spinal NTDs and suggest a new family of proteins involved in the pathogenesis of these malformations.Mounting evidence indicates that the renin-angiotensin (RAS) and immune systems interact with one another in the central nervous system (CNS) and that they are importantly involved in the pathogenesis of hypertension. Components comprising the classic RAS were first identified in the periphery, and subsequently, similar factors were found to be generated de novo in many different organs including the brain. There is humoral-neural coupling between the systemic and brain RASs, which is important for controlling sympathetic tone and the release of endocrine factors that collectively determine blood pressure (BP). Similar to the interactions between the systemic and brain RASs is the communication between the peripheral and brain immune systems. Systemic inflammation activates the brain's immune response. Importantly, the RAS and inflammatory factors act synergistically in brain regions involved in the regulation of BP. This review presents evidence of how such interactions between the brain RAS and central immune mechanisms contribute to the pathogenesis of hypertension. Emphasis focuses on the role of these interactions to induce neuroplastic changes in a central neural network resulting in hypertensive response sensitization (HTRS). link2 Neuroplasticity and HTRS can be induced by challenges (stressors) presented earlier in life such as a low-dose of angiotensin II or high fat diet (HFD) feeding in adults. Similarly, the offspring of mothers with gestational hypertension or of mothers ingesting a HFD during pregnancy are reprogrammed and manifest HTRS when exposed to new stressors as adults. Consideration of the actions and interactions of the brain RAS and inflammatory mediators in the context of the induction and expression of HTRS will provide insights into the etiology of high BP that may lead to new strategies for the prevention and treatment of hypertension.Conditioned context-induced retrieval of drug withdrawal memory contributes to drug relapse. The basolateral amygdala (BLA) is an important brain region that is involved in conditioned context-induced retrieval of morphine withdrawal memory. However, the upstream pathways of the activation of the BLA by conditioned context remains to be studied. The present results show that the CA1 of dorsal hippocampus is an upstream brain region of the activation of the BLA during conditioned context-induced morphine withdrawal memory retrieval; the indirect connection from the CA1 of dorsal hippocampus to the BLA is enhanced in mice with conditioned place aversion (CPA); the postrhinal cortex (POR) is a brain region that connects the CA1 of dorsal hippocampus and the activation of the BLA during conditioned context-induced retrieval of morphine-withdrawal memory. These results suggest that a conditioning-strengthened indirect circuit from the CA1 of dorsal hippocampus to the BLA through the POR participates in morphine withdrawal memory retrieval.Current guidelines regarding treatment for germ-cell tumors (GCTs) emphasizes cautious progression focusing on stage-specific treatments. Presented herein is the case of a 30-year-old man who, through monitoring of serum alpha-fetoprotein (AFP) levels and surveillance imaging, avoided excessive treatment. link3 PF-477736 demonstrates how an experienced clinician, familiar with natural history of GCTs, can appropriately classify level of risk and allow a patient to preserve natural fertility. Furthermore, we highlight the potential for miRNA analysis in staging and management of GCTs. This case serves to underscore the importance of acting with caution in the pursuit of the best outcome for our patients.