Psychedelics for acquired brain injury: a review of molecular mechanisms and therapeutic potential.

Acquired brain injury (ABI), such as traumatic brain injury and stroke, is a leading cause of disability worldwide, resulting in debilitating acute and chronic symptoms, as well as an increased risk of developing neurological and neurodegenerative disorders. These symptoms can stem from various neurophysiological insults, including neuroinflammation, oxidative stress, imbalances in neurotransmission, and impaired neuroplasticity. Despite advancements in medical technology and treatment interventions, managing ABI remains a significant challenge. Emerging evidence suggests that psychedelics may rapidly improve neurobehavioral outcomes in patients with various disorders that share physiological similarities with ABI. However, research specifically focussed on psychedelics for ABI is limited. This narrative literature review explores the neurochemical properties of psychedelics as a therapeutic intervention for ABI, with a focus on serotonin receptors, sigma-1 receptors, and neurotrophic signalling associated with neuroprotection, neuroplasticity, and neuroinflammation. The promotion of neuronal growth, cell survival, and anti-inflammatory properties exhibited by psychedelics strongly supports their potential benefit in managing ABI. Further research and translational efforts are required to elucidate their therapeutic mechanisms of action and to evaluate their effectiveness in treating the acute and chronic phases of ABI.

Measurements of Arterial Occlusion Pressure Using Hand-Held Devices.

ABSTRACT: Vehrs, PR, Reynolds, S, Allen, J, Barrett, R, Blazzard, C, Burbank, T, Hart, H, Kasper, N, Lacey, R, Lopez, D, and Fellingham, GW. Measurements of arterial occlusion pressure using hand-held devices. J Strength Cond Res 38(5): 873-880, 2024-Arterial occlusion pressure (AOP) of the brachial artery was measured simultaneously using Doppler ultrasound (US), a hand-held Doppler (HHDOP), and a pulse oximeter (PO) in the dominant (DOM) and nondominant (NDOM) arms of males ( n = 21) and females ( n = 23) using continuous (CONT) and incremental (INCR) cuff inflation protocols. A mixed-model analysis of variance revealed significant ( p < 0.05) overall main effects between AOP measured using a CONT (115.7 ± 10.9) or INCR (115.0 ± 11.5) cuff inflation protocol; between AOP measured using US (116.3 ± 11.2), HHDOP (115.4 ± 11.2), and PO (114.4 ± 11.2); and between males (120.7 ± 10.6) and females (110.5 ± 9.4). The small overall difference (1.81 ± 3.3) between US and PO measures of AOP was significant ( p < 0.05), but the differences between US and HHDOP and between HHDOP and PO measures of AOP were not significant. There were no overall differences in AOP between the DOM and NDOM arms. Trial-to-trial variance in US measurements of AOP was not significant when using either cuff inflation protocol but was significant when using HHDOP and PO and a CONT cuff inflation protocol. Bland-Altman plots revealed reasonable limits of agreement for both HHDOP and PO measures of AOP. The small differences in US, HHDOP, and PO measurements of AOP when using CONT or INCR cuff inflation protocols are of minimal practical importance. The choice of cuff inflation protocol is one of personal preference. Hand-held Doppler of PO can be used to assess AOP before using blood flow restriction during exercise.

Treatment with the vascular endothelial growth factor-A antibody, bevacizumab, has sex-specific effects in a rat model of mild traumatic brain injury.

Mild traumatic brain injury (mTBI) involves damage to the cerebrovascular system. Vascular endothelial growth factor-A (VEGF-A) is an important modulator of vascular health and VEGF-A promotes the brain's ability to recover after more severe forms of brain injury; however, the role of VEGF-A in mTBI remains poorly understood. Bevacizumab (BEV) is a monoclonal antibody that binds to VEGF-A and neutralises its actions. To better understand the role of VEGF-A in mTBI recovery, this study examined how BEV treatment affected outcomes in rats given a mTBI. Adult Sprague-Dawley rats were assigned to sham-injury + vehicle treatment (VEH), sham-injury + BEV treatment, mTBI + VEH treatment, mTBI + BEV treatment groups. Treatment was administered intracerebroventricularly via a cannula beginning at the time of injury and continuing until the end of the study. Rats underwent behavioral testing after injury and were euthanized on day 11. In both females and males, BEV had a negative impact on cognitive function. mTBI and BEV treatment increased the expression of inflammatory markers in females. In males, BEV treatment altered markers related to hypoxia and vascular health. These novel findings of sex-specific responses to BEV and mTBI provide important insights into the role of VEGF-A in mTBI.

Reelin Rescues Behavioral, Electrophysiological, and Molecular Metrics of a Chronic Stress Phenotype in a Similar Manner to Ketamine.

Over the past decade, ketamine, an NMDA receptor antagonist, has demonstrated fast-acting antidepressant effects previously unseen with monoaminergic-based therapeutics. Concerns regarding psychotomimetic effects limit the use of ketamine for certain patient populations. Reelin, an extracellular matrix glycoprotein, has shown promise as a putative fast-acting antidepressant in a model of chronic stress. However, research has not yet demonstrated the changes that occur rapidly after peripheral reelin administration. To address this key gap in knowledge, male Long-Evans rats underwent a chronic corticosterone (CORT; or vehicle) paradigm (40 mg/kg, 21 d). On day 21, rats were then administered an acute dose of ketamine (10 mg/kg, i.p.), reelin (3 µg, i.v.), or vehicle. Twenty-four hours after administration, rats underwent behavioral or in vivo electrophysiological testing before killing. Immunohistochemistry was used to confirm changes in hippocampal reelin immunoreactivity. Lastly, the hippocampus was microdissected from fresh tissue to ascertain whole cell and synaptic-specific changes in protein expression through Western blotting. Chronic corticosterone induced a chronic stress phenotype in the forced swim test and sucrose preference test (SPT). Both reelin and ketamine rescued immobility and swimming, however reelin alone rescued latency to immobility. In vivo electrophysiology revealed decreases in hippocampal long-term potentiation (LTP) after chronic stress which was increased significantly by both ketamine and reelin. Reelin immunoreactivity in the dentate gyrus paralleled the behavioral and electrophysiological findings, but no significant changes were observed in synaptic-level protein expression. This exploratory research supports the putative rapid-acting antidepressant effects of an acute dose of reelin across behavioral, electrophysiological, and molecular measures.

Acute effects of single and repeated mild traumatic brain injury on levels of neurometabolites, lipids, and mitochondrial function in male rats.

Introduction: Mild traumatic brain injuries (mTBIs) are the most common form of acquired brain injury. Symptoms of mTBI are thought to be associated with a neuropathological cascade, potentially involving the dysregulation of neurometabolites, lipids, and mitochondrial bioenergetics. Such alterations may play a role in the period of enhanced vulnerability that occurs after mTBI, such that a second mTBI will exacerbate neuropathology. However, it is unclear whether mTBI-induced alterations in neurometabolites and lipids that are involved in energy metabolism and other important cellular functions are exacerbated by repeat mTBI, and if such alterations are associated with mitochondrial dysfunction. Methods: In this experiment, using a well-established awake-closed head injury (ACHI) paradigm to model mTBI, male rats were subjected to a single injury, or five injuries delivered 1 day apart, and injuries were confirmed with a beam-walk task and a video observation protocol. Abundance of several neurometabolites was evaluated 24 h post-final injury in the ipsilateral and contralateral hippocampus using in vivo proton magnetic resonance spectroscopy (1H-MRS), and mitochondrial bioenergetics were evaluated 30 h post-final injury, or at 24 h in place of 1H-MRS, in the rostral half of the ipsilateral hippocampus. Lipidomic evaluations were conducted in the ipsilateral hippocampus and cortex. Results: We found that behavioral deficits in the beam task persisted 1- and 4 h after the final injury in rats that received repetitive mTBIs, and this was paralleled by an increase and decrease in hippocampal glutamine and glucose, respectively, whereas a single mTBI had no effect on sensorimotor and metabolic measurements. No group differences were observed in lipid levels and mitochondrial bioenergetics in the hippocampus, although some lipids were altered in the cortex after repeated mTBI. Discussion: The decrease in performance in sensorimotor tests and the presence of more neurometabolic and lipidomic abnormalities, after repeated but not singular mTBI, indicates that multiple concussions in short succession can have cumulative effects. Further preclinical research efforts are required to understand the underlying mechanisms that drive these alterations to establish biomarkers and inform treatment strategies to improve patient outcomes.

Intravenous Reelin Treatment Rescues Atrophy of Spleen White Pulp and Correlates to Rescue of Forced Swim Test Immobility and Neurochemical Alterations Induced by Chronic Stress.

Reelin, an extracellular matrix protein with putative antidepressant-like properties, becomes dysregulated by chronic stress. Improvement in cognitive dysfunction and depression-like behavior induced by chronic stress has been reported with both intrahippocampal and intravenous Reelin treatment but the mechanisms responsible are not clear. To determine if treatment with Reelin modifies chronic stress-induced dysfunction in immune organs and whether this relates to behavioral and/or neurochemical outcomes, spleens were collected from both male (n = 62) and female (n = 53) rats treated with daily corticosterone injections for three weeks that received Reelin or vehicle. Reelin was intravenously administered once on the final day of chronic stress, or repeatedly, with weekly treatments throughout chronic stress. Behavior was assessed during the forced swim test and the object-in-place test. Chronic corticosterone caused significant atrophy of the spleen white pulp, but treatment with a single shot of Reelin restored white pulp in both males and females. Repeated Reelin injections also resolved atrophy in females. Correlations were observed between recovery of white pulp atrophy and recovery of behavioral deficits and expression of both Reelin and glutamate receptor 1 in the hippocampus, supporting a role of the peripheral immune system in the recovery of chronic stress-induced behaviors following treatment with Reelin. Our data adds to research indicating Reelin could be a valuable therapeutic target for chronic stress-related disorders including major depression.

Ketamine and serotonergic psychedelics: An update on the mechanisms and biosignatures underlying rapid-acting antidepressant treatment.

The discovery of ketamine as a rapid-acting antidepressant spurred significant research to understand its underlying mechanisms of action and to identify other novel compounds that may act similarly. Serotonergic psychedelics (SPs) have shown initial promise in treating depression, though the challenge of conducting randomized controlled trials with SPs and the necessity of long-term clinical observation are important limitations. This review summarizes the similarities and differences between the psychoactive effects associated with both ketamine and SPs and the mechanisms of action of these compounds, with a focus on the monoaminergic, glutamatergic, gamma-aminobutyric acid (GABA)-ergic, opioid, and inflammatory systems. Both molecular and neuroimaging aspects are considered. While their main mechanisms of action differ-SPs increase serotonergic signaling while ketamine is a glutamatergic modulator-evidence suggests that the downstream mechanisms of action of both ketamine and SPs include mechanistic target of rapamycin complex 1 (mTORC1) signaling and downstream GABAA receptor activity. The similarities in downstream mechanisms may explain why ketamine, and potentially SPs, exert rapid-acting antidepressant effects. However, research on SPs is still in its infancy compared to the ongoing research that has been conducted with ketamine. For both therapeutics, issues with regulation and proper controls should be addressed before more widespread implementation. This article is part of the Special Issue on "Ketamine and its Metabolites".

Sex differences in basal reelin levels in the paraventricular hypothalamus and in response to chronic stress induced by repeated corticosterone in rats.

Repeated exposure to the stress hormone corticosterone results in depressive-like behaviours paralleled by the downregulation of hippocampal reelin expression. Reelin is expressed in key neural populations involved in the stress response, but whether its hypothalamic expression is sex-specific or involved in sex-specific vulnerability to stress is unknown. Female and male rats were treated with either daily vehicle or corticosterone injections (40 mg/kg) for 21 days. Thereafter, they were subjected to several behavioural tasks before being sacrificed to allow the analysis of reelin expression in hypothalamic nuclei. The basal density of reelin-positive cells in males was significantly higher in the paraventricular nucleus (19 %) and in the medial preoptic area (51 %) compared to females. Chronic corticosterone injections increased the immobility time in the forced swim test in males (107 %) and females (108 %) and decreased the exploration of the elevated plus maze in males (34 %). Corticosterone also caused a significant decrease in the density of reelin-positive cells in males, in both ventrodorsal (37 %) and ventrolateral (32 %) subdivisions of the paraventricular nucleus, while not affecting females. Moreover, in the paraventricular nucleus of males, 30 % of the basal reelin-positive cells co-expressed oxytocin while only 17.5 % did in females, showing a positive correlation between reelin and oxytocin levels. Chronic corticosterone did not significantly affect co-localization levels. For the first time, this study shows that there is a sexually dimorphic subpopulation of reelin-positive neurons in the paraventricular nucleus that can be differentially affected by chronic stress.

Recommendations for Medical and Mental Health Care in Assisted Living Based on an Expert Delphi Consensus Panel: A Consensus Statement.

Importance: Assisted living (AL) is the largest provider of residential long-term care in the US, and the morbidity of AL residents has been rising. However, AL is not a health care setting, and concern has been growing about residents' medical and mental health needs. No guidance exists to inform this care. Objective: To identify consensus recommendations for medical and mental health care in AL and determine whether they are pragmatic. Evidence Review: A Delphi consensus statement study was conducted in 2021; as a separate effort, the extent to which the recommendations are reflected in practice was examined in data obtained from 2016 to 2021 (prepandemic). In the separate effort, data were from a 7-state study (Arkansas, Louisiana, New Jersey, New York, Oklahoma, Pennsylvania, Texas). The 19 Delphi panelists constituted nationally recognized experts in medical, nursing, and mental health needs of and care for older adults; dementia care; and AL and long-term care management, advocacy, regulation, and education. One invitee was unavailable and nominated an alternate. The primary outcome was identification of recommended practices based on consensus ratings of importance. Panelists rated 183 items regarding importance to care quality and feasibility. Findings: Consensus identified 43 recommendations in the areas of staff and staff training, nursing and related services, resident assessment and care planning, policies and practices, and medical and mental health clinicians and care. To determine the pragmatism of the recommendations, their prevalence was examined in the 7-state study and found that most were in practice. The items reflected the tenets of AL, the role of AL in providing dementia care, the need for pragmatism due to the diversity of AL, and workforce needs. Conclusions and Relevance: In this consensus statement, 43 recommendations important to medical and mental health care in AL were delineated that are highly pragmatic as a guide for practice and policy.

Reelin has antidepressant-like effects after repeated or singular peripheral injections.

Chronic stress is a significant risk factor for depression onset. The effects of chronic stress can be studied preclinically using a corticosterone (CORT)-administration paradigm that results in a phenotype of depressive-like behavior associated with neurochemical abnormalities in brain regions like the hippocampus. We have recently shown that intrahippocampal infusions of Reelin have a fast effect in normalizing CORT-induced behavioral and neurochemical alterations. Reelin is also expressed in multiple peripheral systems and is found in blood plasma which prompted us to investigate whether peripheral intravenous (i.v.) Reelin injections could also result in antidepressant (ATD)-like actions. Repeated i.v. injections of Reelin were effective in rescuing the CORT-induced increases in forced-swim-test immobility in male and female rats, decreases in Reelin-immunopositive cells in the dentate gyrus subgranular zone, the expression of hippocampal GABAAß2/3, GluA1, and GluN2B receptors, and serotonin transporter (SERT) membrane protein clustering (MPC) in blood lymphocytes. However, Reelin had only a partial effect on the number and maturation rate of dentate gyrus newborn cells. CORT and Reelin did not affect open field test behavior. After evaluating the effects of multiple Reelin injections, we demonstrated that a single Reelin injection administered at the end of CORT treatment could rescue in 24 h the behavioral (forced-swim-test and object-in-place test), as well as SERT MPC and neurochemical effects of CORT. These findings show that i.v. injections of Reelin have fast ATD-like effects associated with the restoration of hippocampal neurochemical deficits. Although additional mechanistic and pharmacokinetic studies are necessary, our data open the possibility to develop Reelin-based therapeutics with putative fast-ATD activity.

Critical care nurses' perceptions of essential elements for an intensive care liaison or critical care outreach nurse curriculum.

BACKGROUND: For over a decade, patients experiencing clinical deterioration have been attended to by specialised nurses, the most senior of which are intensive care unit liaison nurses (ICU LNs) or critical care outreach nurses. These roles have evolved without consistent and formal recognised educational preparation. To continue to advance patient safety, an understanding of the educational requirements for these vital roles is required. AIM: The aim of this study was to ascertain nurses' perceptions of the curriculum required to perform the roles of ICU LNs or critical care outreach nurses within an acute care sector rapid response system. METHODS: An exploratory descriptive study was conducted at an international rapid response system conference in 2016 following ethics approval. Using convenience sampling, extended response surveys were completed by nurses with rapid response system leadership experience and roles. Data were analysed using content analysis according to a priori themes of theoretical knowledge, skills, and attributes. RESULTS: Seventy-seven registered nurses volunteered to take part in the study, forming 14 groups, each with four to seven members. Participants identified key concepts for desired theoretical knowledge, practical skills, and personal attributes. Professional behaviours were more frequently emphasised than theoretical knowledge or practical skills, suggesting personal attributes were highly valued in these leadership roles. CONCLUSIONS: A curriculum designed to prepare patient safety leadership roles of the ICU LN or critical care outreach nurse has been identified. These findings can inform the development of postgraduate courses and training requirements, along with position descriptions and expectations of employers regarding the skill set expected in these leadership roles.

Patient oriented research in mental health: matching laboratory to life and beyond in Canada.

As patient-oriented research gains popularity in clinical research, the lack of patient input in foundational science grows more evident. Research has shown great utility in active partnerships between patient partners and scientists, yet many researchers are still hesitant about listening to the voices of those with lived experience guide and shape their experiments. Mental health has been a leading area for patient movements such as survivor-led research, however the stigma experienced by these patients creates difficulties not present in other health disciplines. The emergence of COVID-19 has also created unique circumstances that need to be addressed. Through this lens, we have taken experiences from our patient partners, students, and primary investigator to create recommendations for the better facilitation of patient-oriented research in foundational science in Canada. With these guidelines, from initial recruitment and leading to sustaining meaningful partnerships, we hope to encourage other researchers that patient-oriented research is necessary for the future of mental health research and foundational science.

Anger bias in the evaluation of crowds.

People are good at categorizing the emotions of individuals and crowds of faces. People also make mistakes when classifying emotion. When they do so with judgments of individuals, these errors tend to be negatively biased, potentially serving a protective function. For example, a face with a subtle expression is more likely to be categorized as angry than happy. Yet surprisingly little is known about the errors people make when evaluating multiple faces. We found that perceivers were biased to classify faces as angry, especially when evaluating crowds. This amplified bias depended on uncertainty, occurring when categorization was difficult, and it reached peak intensity for crowds with four members. Drift diffusion modeling revealed the mechanisms behind this bias, including an early response component and more efficient processing of anger from crowds with subtle expressions. Our findings introduce bias as an important new dimension for understanding how perceivers make judgments about crowds. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Is all conflict the same? The role of perceived intensity in understanding its effects.

While interpersonal conflict at work continues to draw attention, researchers have rarely considered the role that conflict intensity plays in amplifying individuals' affective reactions to it. Hence, this study examines conflict intensity as a moderator of the relationship between interpersonal conflict and perceived stress, physical symptoms, and job satisfaction, through negative affect. A total of 306 employees from various industries participated in this cross-sectional study. Supporting and expanding an emotion-centered model of conflict, results indicated that the indirect effects of conflict on the study's outcomes were higher when participants perceived the conflict to be of medium and high-level intensity.

Severe life stress, mitochondrial dysfunction, and depressive behavior: A pathophysiological and therapeutic perspective.

Mitochondria are responsible for providing our cells with energy, as well as regulating oxidative stress and apoptosis, and considerable evidence demonstrates that mitochondria-related alterations are prevalent during chronic stress and depression. Here, we discuss how chronic stress may induce depressive behavior by potentiating mitochondrial allostatic load, which ultimately decreases energy production, elevates the generation of harmful reactive oxygen species, damages mitochondrial DNA and increases membrane permeability and pro-apoptotic factor release. We also discuss how mitochondrial insults can exacerbate the immune response, contributing to depressive symptomology. Furthermore, we illustrate how depression symptoms are associated with specific mitochondrial defects, and how targeting of these defects with pharmacological agents may be a promising avenue for the development of novel, more efficacious antidepressants. In summary, this review supports the notion that severe psychosocial stress induces mitochondrial dysfunction, thereby increasing the vulnerability to developing depressive symptoms.

Cyclical administration of corticosterone results in aggravation of depression-like behaviors and accompanying downregulations in reelin in an animal model of chronic stress relevant to human recurrent depression.

Depression is recognized as a highly chronic and recurrent disorder. Each successive episode increases susceptibility to future relapses. The current study aimed to develop an animal model of chronic stress relevant to human recurrent depression in order to examine possible neurobiological mechanisms behind this increased vulnerability. We hypothesized that rats with a prior depression-like episode would be sensitized to subsequent stress, developing depression-like behaviors in response to shorter glucocorticoid exposures. Rats were given corticosterone (CORT) or vehicle injections for one, two, or three 21-day cycles, followed by recovery periods. A series of behavioural assessments were conducted at specific time points after CORT treatment or the recovery period. After behavioral testing, the rats were sacrificed for immunohistochemical analyses of the extracellular matrix protein reelin, which is involved in regulating neural plasticity and is decreased in the hippocampus of depression patients. We found that repeated and cyclic exposure to high levels of CORT escalated depression-like behavior (i.e., forced swim test, sucrose preference test) without altering general locomotor activity (i.e., open field test). Changes in depression-like behaviors were accompanied by cumulative and persistent decreases in reelin-positive cells in the dentate gyrus subgranular zone. These data support the idea of an exacerbation of behavioral and neurochemical alterations with recurrent episodes, which highlights the importance of early therapeutic interventions.

Fast-acting antidepressant-like effects of Reelin evaluated in the repeated-corticosterone chronic stress paradigm.

The present report examines the effects of repeated or single intrahippocampal Reelin infusions on measures of depressive-like behavior, cognition, and hippocampal neurogenesis in the repeated-corticosterone (CORT) paradigm. Rats received subcutaneous injections of CORT for 3 weeks and Reelin was infused through an inserted canula in the left hippocampus on days 7, 14, and 21, or only on day 21 of CORT injections. CORT increased immobility in the forced-swim test and impaired object-location memory. Notably, these effects were reversed by both repeated and single-Reelin infusions. CORT decreased both the number and complexity of doublecortin-labeled maturing newborn neurons in the dentate gyrus subgranular zone, and a single-Reelin infusion increased the number but not complexity of newborn neurons, while repeated Reelin infusions restored both. Injection of the AMPA antagonist CNQX blocked the rescue of the behavioral phenotype by Reelin but did completely block the effects of Reelin on hippocampal neurogenesis. Reelin is able to rescue the deficits in AMPA, NMDA, GABAA receptors, mTOR and p-mTOR induced by CORT. These novel results demonstrate that a single intrahippocampal Reelin infusion into the dorsal hippocampus has fast-acting antidepressant-like effects, and that some of these effects may be at least partially independent of Reelin actions on hippocampal neurogenesis.

Exploring the Potential Antidepressant Mechanisms of TNFα Antagonists.

Human and animal studies suggest an intriguing relationship between the immune system and the development of depression. Some peripherally produced cytokines, such as TNF-α, can cross the blood brain barrier and result in activation of brain microglia which produces additional TNF-α and fosters a cascade of events including decreases in markers of synaptic plasticity and increases in neurodegenerative events. This is exemplified by preclinical studies, which show that peripheral administration of pro-inflammatory cytokines can elicit depression-like behavior. Importantly, this depression-like behavior can be ameliorated by anti-cytokine therapies. Work in our laboratory suggests that TNF-α is particularly important for the development of a depressive phenotype and that TNF-α antagonists might have promise as novel antidepressant drugs. Future research should examine rates of inflammation at baseline in depressed patients and whether anti-inflammatory agents could be included as part of the treatment regimen for depressive disorders.

Changes in Membrane Protein Clustering in Peripheral Lymphocytes in an Animal Model of Depression Parallel Those Observed in Naïve Depression Patients: Implications for the Development of Novel Biomarkers of Depression.

Naïve depression patients show alterations in serotonin transporter (SERT) and serotonin 2A (5HT2A) receptor clustering in peripheral lymphocytes, and these alterations have been proposed as a biomarker of therapeutic efficacy in major depression. Repeated corticosterone (CORT) induces a consistent depression-like phenotype and has been widely used as an animal model to study neurobiological alterations underlying the depressive symptoms. In this experiment, we used the CORT paradigm to evaluate whether depression-like behavior is associated with similar changes in the pattern of SERT and 5HT2A membrane protein clustering as those observed in depression patients. We also analyzed the clustering of other proteins expressed in lipid rafts in lymphocytes. Rats received daily CORT or vehicle injections for 21 consecutive days. Afterward they underwent the forced swim test to evaluate depression-like behavior, and isolated lymphocytes were analyzed by immunocytochemistry coupled to image-analysis to study clustering parameters of the SERT, 5HT2A receptor, dopamine transporter (DAT), Beta2 adrenergic receptor (ß2AR), NMDA 2B receptor (NR2B), Pannexin 1 (Pnx1), and prion cellular protein (PrPc). Our results showed that CORT increases the size of protein clusters for all proteins with the exception of ß 2AR, which is decreased. CORT also increased the number of clusters for Pnx1 and PrPc only. Overall, these results indicate that alterations in SERT and 5HT2A protein clustering in naïve depression patients are paralleled by changes seen in an animal model of depression. The CORT paradigm may be a useful screen for examining additional proteins in lymphocytes as a preliminary step prior to their analysis as biomarkers of depression in human blood samples.

Mitochondria and Mood: Mitochondrial Dysfunction as a Key Player in the Manifestation of Depression.

Human and animal studies suggest an intriguing link between mitochondrial diseases and depression. Although depression has historically been linked to alterations in monoaminergic pharmacology and adult hippocampal neurogenesis, new data increasingly implicate broader forms of dampened plasticity, including plasticity within the cell. Mitochondria are the cellular powerhouse of eukaryotic cells, and they also regulate brain function through oxidative stress and apoptosis. In this paper, we make the case that mitochondrial dysfunction could play an important role in the pathophysiology of depression. Alterations in mitochondrial functions such as oxidative phosphorylation (OXPHOS) and membrane polarity, which increase oxidative stress and apoptosis, may precede the development of depressive symptoms. However, the data in relation to antidepressant drug effects are contradictory: some studies reveal they have no effect on mitochondrial function or even potentiate dysfunction, whereas other studies show more beneficial effects. Overall, the data suggest an intriguing link between mitochondrial function and depression that warrants further investigation. Mitochondria could be targeted in the development of novel antidepressant drugs, and specific forms of mitochondrial dysfunction could be identified as biomarkers to personalize treatment and aid in early diagnosis by differentiating between disorders with overlapping symptoms.