A visual circuit related to the habenula mediates the prevention of cocaine relapse by bright light treatment.

Despite significant advancements in our understanding of addiction at the neurobiological level, a highly effective extinction procedure for preventing relapse remains elusive. In this study, we report that bright light treatment (BLT) administered during cocaine withdrawal with extinction training prevents cocaine-driven reinstatement by acting through the thalamic-habenular pathway. We found that during cocaine withdrawal, the lateral habenula (LHb) was recruited, and inhibition of the LHb via BLT prevented cocaine-driven reinstatement. We also demonstrated that the effects of BLT were mediated by activating LHb-projecting neurons in the ventral lateral geniculate nucleus and intergeniculate leaflet (vLGN/IGL) or by inhibiting postsynaptic LHb neurons. Furthermore, BLT was found to improve aversive emotional states induced by drug withdrawal. Our findings suggest that BLT administered during the cocaine withdrawal may be a promising strategy for achieving drug abstinence.

Effect of transdermal drug delivery therapy on anxiety symptoms in schizophrenic patients.

Objective: To evaluate the efficacy and safety of transdermal drug delivery therapy for schizophrenia with anxiety symptoms. Methods: A total of 80 schizophrenic patients (34 males and 56 females) with comorbid anxiety disorders were randomly assigned to the treatment group (n = 40) and the control group (n = 40) with 6 weeks of follow-up. The patients in the treatment group received the standard antipsychotic drug treatment along with transdermal drug delivery therapy. The evaluation of the patients included the Hamilton Anxiety Scale (HAMA), Hamilton Depression Scale (HAMD-17), and treatment emergent symptom scale (TESS) at baseline, 3 weeks, and 6 weeks after transdermal drug delivery therapy. The Positive and Negative Symptom Scale (PANSS) was assessed at baseline and after 6 weeks of treatment. Results: After 3 and 6 weeks of treatment, the HAMA scale scores in the treatment group were lower than those in the control group (p < 0.001). However, there were no significant differences in the HAMD-17 scale scores, PANSS total scores, and subscale scores between the two groups (p > 0.05). Additionally, no significant differences in adverse effects were observed between the two groups during the intervention period (p > 0.05). After 6 weeks of penetration therapy, there was a low negative correlation between total disease duration and the change in HAMA scale score (pretreatment-posttreatment) in the treatment group. Conclusion: Combined traditional Chinese medicine directed penetration therapy can improve the anxiety symptoms of patients with schizophrenia and has a safe profile.

Hypothalamic Menin regulates systemic aging and cognitive decline.

Aging is a systemic process, which is a risk factor for impaired physiological functions, and finally death. The molecular mechanisms driving aging process and the associated cognitive decline are not fully understood. The hypothalamus acts as the arbiter that orchestrates systemic aging through neuroinflammatory signaling. Our recent findings revealed that Menin plays important roles in neuroinflammation and brain development. Here, we found that the hypothalamic Menin signaling diminished in aged mice, which correlates with systemic aging and cognitive deficits. Restoring Menin expression in ventromedial nucleus of hypothalamus (VMH) of aged mice extended lifespan, improved learning and memory, and ameliorated aging biomarkers, while inhibiting Menin in VMH of middle-aged mice induced premature aging and accelerated cognitive decline. We further found that Menin epigenetically regulates neuroinflammatory and metabolic pathways, including D-serine metabolism. Aging-associated Menin reduction led to impaired D-serine release by VMH-hippocampus neural circuit, while D-serine supplement rescued cognitive decline in aged mice. Collectively, VMH Menin serves as a key regulator of systemic aging and aging-related cognitive decline.

Reduced motor cortex GABABR function following chronic alcohol exposure.

The GABAB receptor (GABABR) agonist baclofen has been used to treat alcohol and several other substance use disorders (AUD/SUD), yet its underlying neural mechanism remains unclear. The present study aimed to investigate cortical GABABR dynamics following chronic alcohol exposure. Ex vivo brain slice recordings from mice chronically exposed to alcohol revealed a reduction in GABABR-mediated currents, as well as a decrease of GABAB1/2R and G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2) activities in the motor cortex. Moreover, our data indicated that these alterations could be attributed to dephosphorylation at the site of serine 783 (ser-783) in GABAB2 subunit, which regulates the surface expression of GABABR. Furthermore, a human study using paired-pulse-transcranial magnetic stimulation (TMS) analysis further demonstrated a reduced cortical inhibition mediated by GABABR in patients with AUD. Our findings provide the first evidence that chronic alcohol exposure is associated with significantly impaired cortical GABABR function. The ability to promote GABABR signaling may account for the therapeutic efficacy of baclofen in AUD.

Targeting neuroinflammation: The therapeutic potential of ω-3 PUFAs in substance abuse.

Substance abuse is a chronic relapsing disorder that results in serious health and socioeconomic issues worldwide. Addictive drugs induce long-lasting morphologic and functional changes in brain circuits and account for the formation of compulsive drug-seeking and drug-taking behaviors. Yet, there remains a lack of reliable therapy. In recent years, accumulating evidence indicated that neuroinflammation was implicated in the development of drug addiction. Findings from both our and other laboratories suggest that ω-3 polyunsaturated fatty acids (PUFAs) are effective in treating neuroinflammation-related mental diseases, and indicate that they could exert positive effects in treating drug addiction. Thus, in the present review, we summarized and evaluated recently published articles reporting the neuroinflammation mechanism in drug addiction and the immune regulatory ability of ω-3 PUFAs. We also sought to identify some of the challenges ahead in the translation of ω-3 PUFAs into addiction treatment.

Muscone Ameliorates LPS-Induced Depressive-Like Behaviors and Inhibits Neuroinflammation in Prefrontal Cortex of Mice.

Depression is partially caused by inflammation in the central nervous system. Early study demonstrated that musk, glandular secretion from male musk deer, exerted an antidepressant-like effect. The aim of this study was to investigate if muscone, a bioactive ingredient in musk, could ameliorate neuroinflammation and depressive-like behaviors as well as explore the potential action mechanism. Mice were intraperitoneally (i.p.) injected with muscone for 2 weeks prior to administration of lipopolysaccharides (LPS, 1mg/kg, i.p.). Pre-treatment with muscone reversed the LPS-induced decrease in body weight within 24h and ameliorated depressive-like behaviors shown by sucrose preference, tail suspension test, and forced swimming test. LPS-induced activation of microglial cells and elevation in expression of inflammatory cytokines including IL-1ß, RANTES, and MCP-1 in the prefrontal cortex of mice were effectively abrogated by muscone, which significantly down-regulated expression of TLR4, MyD88, Caspase-1, NLRP3, renin, and Ang II. In addition, treatment of BV2 microglia cells with muscone markedly attenuated the LPS-induced rise in protein expression of TLR4, Ang II, and IL-1ß. This study revealed that muscone could ameliorate LPS-induced depressive-like behaviors by repressing neuroinflammation in the prefrontal cortex of mice caused by its suppression on microglia activation and production of inflammatory cytokines via acting on TLR4 pathway and RAS cascade.

A Visual Circuit Related to Habenula Underlies the Antidepressive Effects of Light Therapy.

Light plays a pivotal role in the regulation of affective behaviors. However, the precise circuits that mediate the impact of light on depressive-like behaviors are not well understood. Here, we show that light influences depressive-like behaviors through a disynaptic circuit linking the retina and the lateral habenula (LHb). Specifically, M4-type melanopsin-expressing retinal ganglion cells (RGCs) innervate GABA neurons in the thalamic ventral lateral geniculate nucleus and intergeniculate leaflet (vLGN/IGL), which in turn inhibit CaMKIIα neurons in the LHb. Specific activation of vLGN/IGL-projecting RGCs, activation of LHb-projecting vLGN/IGL neurons, or inhibition of postsynaptic LHb neurons is sufficient to decrease the depressive-like behaviors evoked by long-term exposure to aversive stimuli or chronic social defeat stress. Furthermore, we demonstrate that the antidepressive effects of light therapy require activation of the retina-vLGN/IGL-LHb pathway. These results reveal a dedicated retina-vLGN/IGL-LHb circuit that regulates depressive-like behaviors and provide a potential mechanistic explanation for light treatment of depression.

Paricalcitol alleviates lipopolysaccharide-induced depressive-like behavior by suppressing hypothalamic microglia activation and neuroinflammation.

Depression is highly prevalent in patients suffering from chronic inflammatory diseases. Dysregulated neuroinflammation and concomitant activated microglia play a pivotal role in the pathogenesis of depression. Paricalcitol (Pari), a vitamin D2 analogue, has been demonstrated to exert anti-inflammative effects on renal and cardiovascular diseases. In this study, mice were pretreated with Pari before being induced to acute depression-like behaviors by systemic lipopolysaccharide (LPS) injection. To determine the therapeutic effects of Pari, alterations in acute body weight, sucrose preference, forced swimming and tail suspension tests were assessed. Then, alterations of pro-inflammation cytokine IL1-ß level and microglia activity in the hypothalamus, which are involved in the pathophysiology of depression, were examined. The results showed that Pari significantly alleviated systemic LPS injection induced depressive-like behaviors as shown by increased sucrose preference and decreased TST and FST immobility. Pari could specifically regulate microglia-mediated neuroinflammation process and local activity of renin-angiotensin system to exert its anti-depressant effects. This study demonstrated a potential for paricalcitol in treating depressive symptoms induced by systemic inflammation, particularly in patients with chronic hypertension.

Fish oil treatment reduces chronic alcohol exposure induced synaptic changes.

Alcohol addiction is a chronic neuropsychiatric disorder that represents one of the most serious global public health problems. Yet, currently there still lacks an effective pharmacotherapy. Omega-3 polyunsaturated fatty acids (N-3 PUFAs) have exhibited beneficial effects in a variety of neurological disorders, particularly in reversing behavioral deficits and neurotoxicity induced by prenatal alcohol exposure and binge drinking. In the present study, we investigated if fish oil, which is rich in N-3 PUFAs, had beneficial effects on preventing relapse and alleviating withdrawal symptoms after chronic alcohol exposure. Our results demonstrated that fish oil significantly reduced the chronic alcohol exposure-induced aberrant dendritic morphologic changes of the medium-sized spiny neurons in the core and the shell of nucleus accumbens. This inhibited the expression of AMPAR2-lacking AMPARs and their accumulation on the post synaptic membranes of medium-sized spiny neurons and eventually alleviated withdrawal symptoms and alcohol dependence. Our study therefore suggests that N-3 PUFAs are promising for treating withdrawal symptoms and alcohol dependence.

A retinoraphe projection regulates serotonergic activity and looming-evoked defensive behaviour.

Animals promote their survival by avoiding rapidly approaching objects that indicate threats. In mice, looming-evoked defensive responses are triggered by the superior colliculus (SC) which receives direct retinal inputs. However, the specific neural circuits that begin in the retina and mediate this important behaviour remain unclear. Here we identify a subset of retinal ganglion cells (RGCs) that controls mouse looming-evoked defensive responses through axonal collaterals to the dorsal raphe nucleus (DRN) and SC. Looming signals transmitted by DRN-projecting RGCs activate DRN GABAergic neurons that in turn inhibit serotoninergic neurons. Moreover, activation of DRN serotoninergic neurons reduces looming-evoked defensive behaviours. Thus, a dedicated population of RGCs signals rapidly approaching visual threats and their input to the DRN controls a serotonergic self-gating mechanism that regulates innate defensive responses. Our study provides new insights into how the DRN and SC work in concert to extract and translate visual threats into defensive behavioural responses.

Mental Practice Combined with Motor Rehabilitation to Treat Upper Limb Hemiparesis of Post-Stroke Patients: Clinical and Experimental Evidence.

Stroke is one of the major causes of disability in the world. Due to the extended lifetime of the world's population, the number of people affected by stroke has increased substantially over the last years. Stroke may lead to sensorimotor deficits, usually causing hemiplegia or hemiparesia. In order to reduce motor deficits and accelerate functional recovery, MP combined with motor rehabilitation was introduced to the rehabilitation process of post-stroke patients. Evidence has shown that MP combining with motor rehabilitation based on activities of daily living was more effective than conventional motor rehabilitation used per se. This combination proved very useful and effective, with significant results in improvement of motor deficits in post-stroke patients. However, further studies must be conducted to determine specific parameters, such as type of imagery, frequency or duration.

Enriched Endogenous Omega-3 Polyunsaturated Fatty Acids Protect Cortical Neurons from Experimental Ischemic Injury.

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) exert therapeutic potential in a variety of neurological disorders, including ischemic stroke. However, the underlying mechanisms still lack investigation. Here, we report that cultured cortical neurons isolated from fat-1 mice with high endogenous n-3 PUFAs were tolerant to oxygen-glucose deprivation/reperfusion (OGD/R) injury. Fat-1 neurons exhibited significantly attenuated reactive oxygen species (ROS) activation induced by OGD/R injury, upregulated antiapoptotic proteins Bcl-2 and Bcl-xL, and reduced cleaved caspase-3. Exogenous administration of docosahexaenoic acid (DHA), a major component of the n-3 PUFA family, resulted in similar protective effects on cultured cortex neurons. We further verified the protective effects of n-3 PUFAs in vivo, using a mini ischemic model with a reproducible cortical infarct and manifest function deficits by occlusion of the distal branch of the middle cerebral artery with focused femtosecond laser pulses. The Fat-1 animals showed decreased ROS expression and higher level of glutathione in the injured brain, associated with improved functional recovery. We therefore provide evidence that n-3 PUFAs exert their protective effects against ischemic injury both in vitro and in vivo, partly through inhibiting ROS activation.

Comparison of the Effects of Contralaterally Controlled Functional Electrical Stimulation and Neuromuscular Electrical Stimulation on Upper Extremity Functions in Patients with Stroke.

BACKGROUND: Contralaterally controlled functional electrical stimulation (CCFES) is an innovative method to improve upper extremity functions after stroke. OBJECTIVE: To compare the effects of CCFES versus neuromuscular electrical stimulation (NMES) on the upper extremity functions in patients with stroke. METHODS: Sixty patients with stroke were randomly assigned into CCFES group (n=30) or NMES group (n=30). All patients were also treated with conventional medical treatment and rehabilitation training. Patients in CCFES group received CCFES to the affected wrist extensors while the NMES group received NMES. The stimulus current was biphasic wave with a pulse duration of 200 µs and a frequency of 60 Hz. The electrical stimulation lasted for 20 min per session, 5 sessions per week for 3 weeks. The intensity of the CCFES was based on the electromyography (EMG) value of the unaffected side while the subjects voluntarily extended their unaffected wrist slightly (<10% range of motion, ROM), moderately (about 50% ROM) and completely (100% ROM). Fugl-Meyer assessment (FMA), motricity index (MI), the Hong Kong version of functional test for the hemiplegic upper extremity (FTHUE-HK) and active range of motion (AROM) of wrist extension were measured before and after 3 weeks of treatment. RESULTS: Compared with the baseline values, both groups showed significant improvements in all the measurements after treatment (p<0.05). Patients in CCFES group showed significantly higher upper extremity FMA, FTHUE-HK scores and AROM of wrist extension than those in NMES group (p<0.05). CONCLUSION: Compared with the conventional NMES, CCFES provides better recovery of upper extremity function in patients with stroke.

Effects of Aerobic Exercise on Anxiety Disorders: A Systematic Review.

Anxiety disorders are the most common psychiatric disorders observed currently. It is a normal adaptive response to stress that allows coping with adverse situations. Nevertheless, when anxiety becomes excessive or disproportional in relation to the situation that evokes it or when there is not any special object directed at it, such as an irrational dread of routine stimuli, it becomes a disabling disorder and is considered to be pathological. The traditional treatment used is medication and cognitive behavioral psychotherapy, however, last years the practice of physical exercise, specifically aerobic exercise, has been investigated as a new non-pharmacological therapy for anxiety disorders. Thus, the aim of this article was to provide information on research results and key chains related to the therapeutic effects of aerobic exercise compared with other types of interventions to treat anxiety, which may become a useful clinical application in a near future. Researches have shown the effectiveness of alternative treatments, such as physical exercise, minimizing high financial costs and minimizing side effects. The sample analyzed, 66.8% was composed of women and 80% with severity of symptoms anxiety as moderate to severe. The data analyzed in this review allows us to claim that alternative therapies like exercise are effective in controlling and reducing symptoms, as 91% of anxiety disorders surveys have shown effective results in treating. However, there is still disagreement regarding the effect of exercise compared to the use of antidepressant symptoms and cognitive function in anxiety, this suggests that there is no consensus on the correct intensity of aerobic exercise as to achieve the best dose-response, with intensities high to moderate or moderate to mild.

Comparison Among Aerobic Exercise and Other Types of Interventions to Treat Depression: A Systematic Review.

Depression is a common and disabling disease that affects over 100 million people worldwide and can have a significant impact on physical and mental health, reducing their quality of life. Thus, the aim of this article was to provide information on research results and key chains related to the therapeutic effects of chronic aerobic exercise compared with other types of interventions to treat depression, which may become a useful clinical application in a near future. Researches have shown the effectiveness of alternative treatments, such as physical exercise, minimizing high financial costs and minimizing side effects. In this review, the data analyzed allows us to claim that alternative therapies, such as exercise, are effective on controlling and reducing symptoms. 69.3% of the studies that investigated the antidepressant effects of exercise on depressive were significant, and the other 30.7% of the studies improved only in general physiological aspects, such as increased oxygen uptake, increased use of blood glucose and decreased body fat percentage, with no improvement on symptoms of depression. From the sample analyzed, 71.4% was composed of women, and regarding the severity of symptoms, 85% had mild to moderate depression and only 15% had moderate to severe depression. However, there is still disagreement regarding the effect of exercise compared to the use of antidepressants in symptomatology and cognitive function in depression, this suggests that there is no consensus on the correct intensity of aerobic exercise as to achieve the best dose-response, with intensities high to moderate or moderate to mild.

Co-enzyme Q10 to treat neurological disorders: basic mechanisms, clinical outcomes, and future research direction.

Coenzyme Q10 (CoQ10) is critical for the cell power supply in mitochondria. CoQ10 shuttles electrons from complexes I and II to complex III, and can be anti-oxdiative. Neurons require high energy for synaptic transmission and therefore the mitochondria dysfunction often leads to severe neuronal degeneration, as observed in many neurological disorders. CoQ10 supplementation has been widely used to treat aging, stroke, neuromuscular diseases, Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, autosomal recessive cerebellar ataxias, Huntington's disease and amyotrophic lateral sclerosis. Here we discuss a large number of preclinical and clinical trials for CoQ10 to elucidate the mechanisms underlying CoQ10 therapy. The rational applications as a therapeutic agent in neurological disorders are discussed.

Adult neurogenesis in the hypothalamus: evidence, functions, and implications.

Neurogenesis occurs in the adult brain in a constitutive manner under physiological circumstances within two regions: the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles. In contrast to these two so-called neurogenic areas, other regions of the brain were considered to be primarily non-neurogenic in nature, implying that no new neurons were formed there under normal conditions. Recently, low proliferative activity was reported in the hypothalamus and the cell layers surrounding the third ventricle. This review summarizes recent evidence for adult neurogenesis in the hypothalamus, and points out the potential contributions of these new neurons to neural processing. We also discussed some technical considerations in investigating neurogenesis in the adult hypothalamus. It is believed that the hypothalamus could serve as a new source and target for stem cell transplantation.

Traditional Chinese Medicine in treatments to depression.

Traditional Chinese Medicine (TCM) has a long history of more than 5,000 years and it has the earliest medicine book in the world: Yellow Emperor's Canon: Internal Medicine (Huang Ti Nei Jing), by the Yellow Emperor of China (2695-2589 BC) (Lin , 1988; Shampo and Kyle, 1989; Wang, 1999). However the combinational and systemic recipes that bring TCM high efficiency also block the promotion of TCM treatment to various diseases, including depression. In this short comment we firstly give some theoretical basis for TCM treatment to depression, then some clinical reports on efficiency; we also present some possible explanations on TCM treatments to depression.