Brain circuits between medial prefrontal cortex (mPFC) and amygdala have been implicated in cortical control of emotion, especially anxiety. Studies in recent years focus on differential roles of ...subregions of mPFC and amygdala, and reciprocal pathways between mPFC and amygdala in regulation of emotional behaviors. It has been shown that, while the projection from ventral mPFC to basomedial amygdala has an anxiolytic effect, the reciprocal projections between dorsal mPFC (dmPFC) and basolateral amygdala (BLA) are generally involved in an anxiogenic effect in various conditions with increased anxiety. However, the function of the projection from dmPFC to BLA in regulation of general emotional behaviors under normal conditions remains unclear. In this study, we used optogenetic analysis to identify how this dmPFC-BLA pathway regulates various emotional behaviors in normal rats. We found that optogenetic stimulation of the dmPFC-BLA pathway promoted a behavioral state of negative emotion, increasing anxiety-like and depressive-like behaviors and producing aversive behavior of place avoidance. Conversely, optogenetic inhibition of this pathway produced opposite effects, reducing anxiety-like and depressive-like behaviors, and inducing behaviors of place preference of reward. These findings suggest that activity of the dmPFC-BLA pathway is sufficient to drive a negative emotion state and the mPFC-amygdala circuit is tonically active in cortical regulation of emotional behaviors.
The amygdala is a critical brain site for regulation of emotion-associated behaviors such as pain and anxiety. Recent studies suggest that differential cell types and synaptic circuits within the ...amygdala complex mediate interacting and opposing effects on emotion and pain. However, the underlying cellular and circuit mechanisms are poorly understood at present. Here we used optogenetics combined with electrophysiological analysis of synaptic inputs to investigate pain-induced synaptic plasticity within the amygdala circuits in rats. We found that 50% of the cell population in the lateral division of the central nucleus of the amygdala (CeAl) received glutamate inputs from both basolateral amygdala (BLA) and from the parabrachial nucleus (PBN), and 39% of the remaining CeAl cells received glutamate inputs only from PBN. Inflammatory pain lasting 3 days, which induced anxiety, produced sensitization in synaptic activities of the BLA-CeAl-medial division of CeA (CeAm) pathway primarily through a postsynaptic mechanism. Moreover, in CeAl cells receiving only PBN inputs, pain significantly augmented the synaptic strength of the PBN inputs. In contrast, in CeAl cells receiving both BLA and PBN inputs, pain selectively increased the synaptic strength of BLA inputs, but not the PBN inputs. Electrophysiological analysis of synaptic currents showed that the increased synaptic strength in both cases involved a postsynaptic mechanism. These findings reveal two main populations of CeAl cells that have differential profiles of synaptic inputs and show distinct plasticity in their inputs in response to anxiety-associated pain, suggesting that the specific input plasticity in the two populations of CeAl cells may encode a different role in amygdala regulation of pain and emotion.
Chronic pain with comorbid emotional disorders is a prevalent neurological disease in patients under various pathological conditions, yet patients show considerable difference in their vulnerability ...to developing chronic pain. Understanding the neurobiological basis underlying this pain vulnerability is essential to develop targeted therapies of higher efficiency in pain treatment of precision medicine. However, this pain vulnerability has not been addressed in preclinical pain research in animals to date. In this study, we investigated individual variance in both sensory and affective/emotional dimensions of pain behaviors in response to chronic neuropathic pain condition in a mouse model of chronic pain. We found that mice displayed considerably diverse sensitivities in the chronic pain-induced anxiety- and depression-like behaviors of affective pain. Importantly, the mouse group that was more vulnerable to developing anxiety was also more vulnerable to developing depressive behavior under the chronic pain condition. In contrast, there was relatively much less variance in individual responses in the sensory dimension of pain sensitization. Molecular analysis revealed that those mice vulnerable to developing the emotional disorders showed a significant reduction in the protein level of DNA methyltransferase 3a in the emotion-processing central nucleus of the amygdala. In addition, social stress also revealed significant individual variance in anxiety behavior in mice. These findings suggest that individual pain vulnerability may be inherent mostly in the emotional/affective component of chronic pain and remain consistent in different aspects of negative emotion, in which adaptive changes in the function of DNA methyltransferase 3a for DNA methylation in central amygdala may play an important role. This may open a new avenue of basic research into the neurobiological mechanisms underlying pain vulnerability.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Attention deficit/hyperactivity disorder （ADHD） is charac-terized by hyperactivity, impaired sustained attention, im- pulsivity, and is usually accompanied by varying degrees of learning difficulties ...and lack of motor coordination. However, the pathophysiology and etiology of ADHD remain inconclusive so far. Our previous studies have demonstrated that the gamma aminobutyric acid transport- er subtype 1 （GAT1） gene knockout （ko） mouse （gatl-/-） is hyperactive and exhibited impaired memory performance in the Morris water maze. In the current study, we found that the gatl-/- mice showed low levels of attentional fo- cusing and increased impulsivity. In addition, the gatl-~- mice displayed ataxia characterized by defects in motor co-ordination and balance skills. The hyperactivity in the ko mice was reduced by both methylphenidate and amphet- amine. Collectively, these results suggest that GAT1 ko mouse is a new animal model for ADHD studying and GAT1 may be a new target to treat ADHD.
Background and object
Heart failure is one of the common complications in patients with end-stage renal disease (ESRD) and a major cause of death in these patients. The choice of dialysis modality ...for ESRD patients with congestive heart failure (CHF) is still inconclusive. The purpose of this study was to compare the prognosis of hemodialysis (HD) and peritoneal dialysis (PD) among ESRD patients with CHF and provide a basis for clinical decision-making.
Materials and methods
This was a retrospective study conducted at Guangdong Provincial Hospital of Traditional Chinese Medicine that included patients with CHF requiring long-term renal replacement therapy between January 1, 2012 and December 31, 2017. The end of follow-up was December 31, 2020. All patients were divided into HD and PD groups and sub grouped by age, and we used univariate and multifactorial Cox regression analyses to calculate the relative hazard ratios (HR) of the different dialysis types and adjusted for differences in baseline data using propensity score matching (PSM).
Result
A total of 121 patients with PD and 156 patients with HD were included in this study. Among younger ESRD patients (≤65 years of age) with CHF, the prognosis of HD was worse than that of PD HR = 1.84, 95% confidence interval (CI) = 1.01–3.34, and this disadvantage remained significant in the fully adjusted model sex, age at dialysis initiation, Charlson comorbidities index, body mass index, prealbumin, hemoglobin, and left ventricular ejection fraction (LVEF) and after PSM. In the older group (>65 years of age), the prognosis of HD was better than that of PD (HR = 0.46, 95% CI = 0.25–0.85), and the protective effect remained in the fully adjusted model and after PSM. The aforementioned survival differences across the cohort were maintained in patients with preserved LVEF (>55%), but could not be reproduced in patients with reduced LVEF (≤55%).
Conclusion
In southern China, PD is a better choice for younger patients with ESRD, CHF and preserved LVEF, and HD is the better option for older patients.
γ-Aminobutyric acid （GABA） is the major inhibitory neurotransmitter in the central nervous system. The termination of GABA transmission is through the action of a family of membrane proteins, called ...GABA transporters （GAT1-4）. It is well established that GABA system is involved in the modulation of memory. Our previous study showed that homozygous GAT1^-/- mice exhibited impaired hippocampus-dependent learning and memory. To evaluate the impact of endogenous reduced GABA reuptake on mice cognitive behaviors, the ability of learning and memory of heterozygous GAT1^＋/- mice was detected by the passive avoidance paradigm and Morris water maze. The hole board paradigm was also used to measure changes in anxiety-related behavior or exploratory behav- ior in such mice. As one form of synaptic plasticity, long- term potentiation was recorded in the mouse hippocampal CA1 area. We found that GAT1^＋/- mice displayed increased learning and memory, decreased anxiety-like behaviors, and highest synaptic plasticity compared with wild-type and homozygous GAT1^-/- mice. Our results suggest that a moderate reduction in GAT1 activity causes the enhancement of learning and memory in mice.
Chronic pain is a common neurological disease involving lasting, multifaceted maladaptations ranging from gene modulation to synaptic dysfunction and emotional disorders. Sustained pathological ...stimuli in many diseases alter the output activities of certain genes through epigenetic modifications, but it is unclear how epigenetic mechanisms operate in the development of chronic pain. We show here that in the rat brainstem nucleus raphe magnus, which is important for central mechanisms of chronic pain, persistent inflammatory and neuropathic pain epigenetically suppresses Gad2 (encoding glutamic acid decarboxylase 65 (GAD65)) transcription through histone deacetylase (HDAC)-mediated histone hypoacetylation, resulting in impaired γ-aminobutyric acid (GABA) synaptic inhibition. Gad2 knockout mice showed sensitized pain behavior and impaired GABA synaptic function in their brainstem neurons. In wild-type but not Gad2 knockout mice, HDAC inhibitors strongly increased GAD65 activity, restored GABA synaptic function and relieved sensitized pain behavior. These findings suggest GAD65 and HDACs as potential therapeutic targets in an epigenetic approach to the treatment of chronic pain.
Full text
Available for:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Overexpression of REST has been implicated in brain tumors, ischemic insults, epilepsy, and movement disorders such as Huntington's disease. However, owing to the lack of a conditional REST ...overexpression animal model, the mechanism of action of REST overexpression in these disorders has not been established in vivo. We created a REST overexpression mouse model using the human REST (hREST) gene. Our results using these mice confirm that hREST expression parallels endogenous REST expression in embryonic mouse brains. Further analyses indicate that REST represses the dopamine receptor 2 (Drd2) gene, which encodes a critical nigrostriatal receptor involved in regulating movement, in vivo. Overexpression of REST using Drd2-Cre in adult mice results in increased REST and decreased DRD2 expression in the striatum, a major site of DRD2 expression, and phenocopies the spontaneous locomotion deficits seen upon global DRD2 deletion or specific DRD2 deletion from indirect-pathway medium spiny neurons. Thus, our studies using this mouse model not only reveal a new function of REST in regulating spontaneous locomotion but also suggest that REST overexpression in DRD2-expressing cells results in spontaneous locomotion deficits.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Objective. To evaluate the effectiveness and safety of Shenfu injection (SFI) for intradialytic hypotension (IDH). Methods. A systematic review of data sources published as of April 2014 was ...conducted. These included the Cochrane Central Register of Controlled Trials (2014 issue 4), Pubmed, Embase, CBM, CNKI, VIP, and Wangfang Data. Randomized controlled trials (RCTs) involving SFI for treatment and prevention of IDH were identified. Two researchers independently selected articles, extracted data, assessed quality, and cross checked the results. Revman 5.2 was used to analyze the results. Results. Eight RCTs were included. The meta-analysis indicated that compared with conventional therapies alone, SFI could elevate systolic blood pressure (SBP), increase the clinical effective rate, decrease the incidence of hypotension, increase serum albumin (ALB) levels, and reduce C-reactive protein (CRP) levels without serious adverse effects. GRADE Quality of Evidence. the quality of SBP, the effective rate, ALB, and CRP were low, and hypotension incidence and DBP were very low. Conclusions. SFI is more effective than conventional therapies for prevention and treatment of IDH. However, a clinical recommendation is not warranted due to the small number of studies included and low methodology quality. Multi-center and high-quality RCTs with large sample sizes are needed to provide stronger evidence.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK, VSZLJ
PDF
