Rajas P. Kale

Stress, inflammation, and cellular vulnerability during early stages of affective disorders: biomarker strategies and opportunities for prevention and intervention

The mood disorder prodrome is conceptualized as a symptomatic, but not yet clinically diagnosable stage of an affective disorder. Although a growing area, more focused research is needed in the pediatric population to better characterize psychopathological symptoms and biological markers that can reliably identify this very early stage in the evolution of mood disorder pathology. Such information will facilitate early prevention and intervention, which has the potential to affect a person’s disease course. This review focuses on the prodromal characteristics, risk factors, and neurobiological mechanisms of mood disorders. In particular, we consider the influence of early-life stress, inflammation, and allostatic load in mediating neural mechanisms of neuroprogression. These inherently modifiable factors have known neuroadaptive and neurodegenerative implications, and consequently may provide useful biomarker targets. Identification of these factors early in the course of the disease will accordingly allow for the introduction of early interventions which augment an individual’s capacity for psychological resilience through maintenance of synaptic integrity and cellular resilience. A targeted and complementary approach to boosting both psychological and physiological resilience simultaneously during the prodromal stage of mood disorder pathology has the greatest promise for optimizing the neurodevelopmental potential of those individuals at risk of disabling mood disorders.

Nucleus accumbens deep-brain stimulation efficacy in ACTH-pretreated rats: alterations in mitochondrial function relate to antidepressant-like effects

Mitochondrial dysfunction has a critical role in the pathophysiology of mood disorders and treatment response. To investigate this, we established an animal model exhibiting a state of antidepressant treatment resistance in male Wistar rats using 21 days of adrenocorticotropic hormone (ACTH) administration (100 μg per day). First, the effect of ACTH treatment on the efficacy of imipramine (10 mg kg−1) was investigated alongside its effect on the prefrontal cortex (PFC) mitochondrial function. Second, we examined the mood-regulatory actions of chronic (7 day) high-frequency nucleus accumbens (NAc) deep-brain stimulation (DBS; 130 Hz, 100 μA, 90 μS) and concomitant PFC mitochondrial function. Antidepressant-like responses were assessed in the open field test (OFT) and forced swim test (FST) for both conditions. ACTH pretreatment prevented imipramine-mediated improvement in mobility during the FST (P<0.05). NAc DBS effectively improved FST mobility in ACTH-treated animals (P<0.05). No improvement in mobility was observed for sham control animals (P>0.05). Analyses of PFC mitochondrial function revealed that ACTH-treated animals had decreased capacity for adenosine triphosphate production compared with controls. In contrast, ACTH animals following NAc DBS demonstrated greater mitochondrial function relative to controls. Interestingly, a proportion (30%) of the ACTH-treated animals exhibited heightened locomotor activity in the OFT and exaggerated escape behaviors during the FST, together with general hyperactivity in their home-cage settings. More importantly, the induction of this mania-like phenotype was accompanied by overcompensative increased mitochondrial respiration. Manifestation of a DBS-induced mania-like phenotype in imipramine-resistant animals highlights the potential use of this model in elucidating mechanisms of mood dysregulation.

Evolution of optogenetic microdevices

Abstract. Implementation of optogenetic techniques is a recent addition to the neuroscientists’ preclinical research arsenal, helping to expose the intricate connectivity of the brain and allowing for on-demand direct modulation of specific neural pathways. Developing an optogenetic system requires thorough investigation of the optogenetic technique and of previously fabricated devices, which this review accommodates. Many experiments utilize bench-top systems that are bulky, expensive, and necessitate tethering to the animal. However, these bench-top systems can make use of power-demanding technologies, such as concurrent electrical recording. Newer portable microdevices and implantable systems carried by freely moving animals are being fabricated that take advantage of wireless energy harvesting to power a system and allow for natural movements that are vital for behavioral testing and analysis. An investigation of the evolution of tethered, portable, and implantable optogenetic microdevices is presented, and an analysis of benefits and detriments of each system, including optical power output, device dimensions, electrode width, and weight is given. Opsins, light sources, and optical fiber coupling are also discussed to optimize device parameters and maximize efficiency from the light source to the fiber, respectively. These attributes are important considerations when designing and developing improved optogenetic microdevices.

Validation of a Portable Low-Power Deep Brain Stimulation Device Through Anxiolytic Effects in a Laboratory Rat Model

Deep brain stimulation (DBS) devices deliver electrical pulses to neural tissue through an electrode. To study the mechanisms and therapeutic benefits of deep brain stimulation, murine preclinical research is necessary. However, conducting naturalistic long-term, uninterrupted animal behavioral experiments can be difficult with bench-top systems. The reduction of size, weight, power consumption, and cost of DBS devices can assist the progress of this research in animal studies. A low power, low weight, miniature DBS device is presented in this paper. This device consists of electronic hardware and software components including a low-power microcontroller, an adjustable current source, an n-channel metal–oxide–semiconductor field-effect transistor, a coin-cell battery, electrode wires and a software program to operate the device. Evaluation of the performance of the device in terms of battery lifetime and device functionality through bench and in vivo tests was conducted. The bench test revealed that this device can deliver continuous stimulation current pulses of strength

Portable closed-loop optogenetic stimulation device

200~\mu \text {A}

A review of brain insulin signaling in mood disorders: From biomarker to clinical target

, width

Revolutionizing Causal Circuitry Neurostimulation Utilizing the Optogenetic Technique Through Advanced Microsystems Development

90~\mu \text {s}

Physiological Monitoring in Deep Brain Stimulation: Toward Closed-Loop Neuromodulation Therapies

, and frequency 130 Hz for over 22 days. The in vivo tests demonstrated that chronic stimulation of the nucleus accumbens (NAc) with this device significantly increased psychomotor activity, together with a dramatic reduction in anxiety-like behavior in the elevated zero-maze test.

Electrical resistance increases at the tissue-electrode interface as an early response to nucleus accumbens deep brain stimulation

This paper presents a closed-loop optogenetic stimulation device to achieve online modulation of neurons. The device is designed to be mountable on small rodents in pre-clinical settings. Considering the size of rodents and the need for portability, a single-piece self-contained device is developed which allows real-time photostimulation based on detected neuronal states. It consists of three components: a neural recorder, a control algorithm, and an optogenetic stimulator. The neural recorder which is realized by analogue circuitry measures the neural signal. The on-off control algorithm analyses the neural signal and controls the stimulation of the target neurons. The optogenetic stimulator performs sampling and digitization of the detected neural signal, runs the control algorithm, and manages the operation of the light source. The configurable neural recorder is capable of 64 dB amplification in the frequency range of 300 Hz to 6 KHz. The outcome of bench testing of the device is reported. The device is portable and headmountable which makes it suitable for use with small rodents in pre-clinical trials.This paper presents a closed-loop optogenetic stimulation device to achieve online modulation of neurons. The device is designed to be mountable on small rodents in pre-clinical settings. Considering the size of rodents and the need for portability, a single-piece self-contained device is developed which allows real-time photostimulation based on detected neuronal states. It consists of three components: a neural recorder, a control algorithm, and an optogenetic stimulator. The neural recorder which is realized by analogue circuitry measures the neural signal. The on-off control algorithm analyses the neural signal and controls the stimulation of the target neurons. The optogenetic stimulator performs sampling and digitization of the detected neural signal, runs the control algorithm, and manages the operation of the light source. The configurable neural recorder is capable of 64 dB amplification in the frequency range of 300 Hz to 6 KHz. The outcome of bench testing of the device is reported. The device is portable and headmountable which makes it suitable for use with small rodents in pre-clinical trials.

Wireless Optogenetics: An Exploration of Portable Microdevices for Small Animal Photostimulation

HIGHLIGHTSCentral insulin signaling is an important moderator of synaptic plasticity.Central insulin regulates mood, memory and cognition.Stress and inflammation are important common pathways in mood and metabolic disorders. ABSTRACT Patients with mood disorders are at increased risk for metabolic dysfunction. Co‐occurrence of the two conditions is typically associated with a more severe disease course and poorer treatment outcomes. The specific pathophysiological mechanisms underlying this bidirectional relationship between mood and metabolic dysfunction remains poorly understood. However, it is likely that impairment of metabolic processes within the brain play a critical role. The insulin signaling pathway mediates metabolic homeostasis and is important in the regulation of neurotrophic and synaptic plasticity processes, including those involved in neurodegenerative diseases like Alzheimer’s. Thus, insulin signaling in the brain may serve to link metabolic function and mood. Central insulin signaling is mediated through locally secreted insulin and widespread insulin receptor expression. Here we review the preclinical and clinical data addressing the relationships between central insulin signaling, cellular metabolism, neurotrophic processes, and mood regulation, including key points of mechanistic overlap. These relationships have important implications for developing biomarker‐based diagnostics and precision medicine approaches to treat severe mood disorders.