Timing matters: Using optogenetics to chronically manipulate neural circuitry and rhythms

The ability to probe defined neural circuits with both the spatial and temporal resolution imparted by optogenetics has transformed the field of neuroscience. Although much attention has been paid to the advantages of manipulating neural activity at millisecond timescales in order to elicit time-locked neural responses, little consideration has been given to the manipulation of circuit activity at physiologically relevant times of day, across multiple days. Nearly all biological events are governed by the circadian clock and exhibit 24 h rhythms in activity. Indeed, neural circuit activity itself exhibits a daily rhythm with distinct temporal peaks in activity occurring at specific times of the day. Therefore, experimentally probing circuit function within and across physiologically relevant time windows (minutes to hours) in behaving animals is fundamental to understanding the function of any one particular circuit within the intact brain. Furthermore, understanding how circuit function changes with repeated manipulation is important for modeling the circuit-wide disruptions that occur with chronic disease states. Here, we review recent advances in optogenetic technology that allow for chronic, temporally specific, control of circuit activity and provide examples of chronic optogenetic paradigms that have been utilized in the search for the neural circuit basis of behaviors relevant to human neuropsychiatric disease. © 2014 Sidor and McClung

Sub-threshold depression and antidepressants use in a community sample: searching anxiety and finding bipolar disorder

<p>Abstract</p> <p>Background</p> <p>To determine the use of antidepressants (ADs) in people with sub-threshold depression (SD); the lifetime prevalence of mania and hypomania in SD and the link between ADs use, bipolarity and anxiety disorders in SD.</p> <p>Methods</p> <p>Study design: community survey. Study population: samples randomly drawn, after stratification from the adult population of municipal records. Sample size: 4999 people from seven areas within six Italian regions. Tools: Questionnaire on psychotropic drug consumption, prescription; Structured Clinical Interview NP for DSM-IV modified (ANTAS); Hamilton Depression Rating Scale (HAM-D); Mood Disorder Questionnaire (MDQ); Short Form Health Survey (SF-12). SD definition: HAM-D > 10 without lifetime diagnosis of Depressive Episode (DE).</p> <p>Results</p> <p>SD point prevalence is 5.0%. The lifetime prevalence of mania and hypomania episodes in SD is 7.3%. Benzodiazepines (BDZ) consumption in SD is 24.1%, followed by ADs (19.7%). In SD, positive for MDQ and comorbidity with Panic Disorder (PD) or Generalized Anxiety Disorders (GAD) are associated with ADs use, whereas the association between a positive MDQ and ADs use, without a diagnosis of PD or GAD, is not significant. Only in people with DE the well-being (SF-12) is higher among those using first-line antidepressants compared to those not using any medication. In people with SD no significant differences were found in terms of SF-12 score according to drug use.</p> <p>Conclusions</p> <p>This study suggests caution in prescribing ADs to people with SD. In people with concomitant anxiety disorders and SD, it should be mandatory to perform a well-designed assessment and evaluate the presence of previous manic or hypomanic symptoms prior to prescribing ADs.</p

Anti-α-Internexin Autoantibody from Neuropsychiatric Lupus Induce Cognitive Damage via Inhibiting Axonal Elongation and Promote Neuron Apoptosis

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a major complication for lupus patients, which often leads to cognitive disturbances and memory loss and contributes to a significant patient morbidity and mortality. The presence of anti-neuronal autoantibodies (aAbs) has been identified; as examples, anti-NMDA receptors and anti-Ribsomal P aAbs have been linked to certain pathophysiological features of NPSLE.In the current study, we used a proteomic approach to identify an intermediate neurofilament alpha-internexin (INA) as a pathogenetically relevant autoantigen in NPSLE. The significance of this finding was then validated in an expanded of a cohort of NPSLE patients (n = 67) and controls (n = 270) by demonstrating that high titers of anti-INA aAb was found in both the serum and cerebrospinal fluid (CSF) of ∼50% NPSLE. Subsequently, a murine model was developed by INA immunization that resulted in pronounced cognitive dysfunction that mimicked features of NPSLE. Histopathology in affected animals displayed cortical and hippocampal neuron apoptosis. In vitro studies further demonstrated that anti-INA Ab mediated neuronal damage via inhibiting axonal elongation and eventually driving the cells to apoptosis.Taken together, this study identified a novel anti-neurofilament aAb in NPSLE, and established a hitherto undescribed mechanism of aAb-mediated neuron damage that could have relevance to the pathophysiology of NPSLE