The Stress-Induced Transcription Factor NR4A1 Adjusts Mitochondrial Function and Synapse Number in Prefrontal Cortex.

The energetic costs of behavioral chronic stress are unlikely to be sustainable without neuronal plasticity. Mitochondria have the capacity to handle synaptic activity up to a limit before energetic depletion occurs. Protective mechanisms driven by the induction of neuronal genes likely evolved to buffer the consequences of chronic stress on excitatory neurons in prefrontal cortex (PFC), as this circuitry is vulnerable to excitotoxic insults. Little is known about the genes involved in mitochondrial adaptation to the buildup of chronic stress. Using combinations of genetic manipulations and stress for analyzing structural, transcriptional, mitochondrial, and behavioral outcomes, we characterized NR4A1 as a stress-inducible modifier of mitochondrial energetic competence and dendritic spine number in PFC. NR4A1 acted as a transcription factor for changing the expression of target genes previously involved in mitochondrial uncoupling, AMP-activated protein kinase activation, and synaptic growth. Maintenance of NR4A1 activity by chronic stress played a critical role in the regressive synaptic organization in PFC of mouse models of stress (male only). Knockdown, dominant-negative approach, and knockout of Nr4a1 in mice and rats (male only) protected pyramidal neurons against the adverse effects of chronic stress. In human PFC tissues of men and women, high levels of the transcriptionally active NR4A1 correlated with measures of synaptic loss and cognitive impairment. In the context of chronic stress, prolonged expression and activity of NR4A1 may lead to responses of mitochondria and synaptic connectivity that do not match environmental demand, resulting in circuit malfunction between PFC and other brain regions, constituting a pathological feature across disorders.SIGNIFICANCE STATEMENT The bioenergetic cost of chronic stress is too high to be sustainable by pyramidal prefrontal neurons. Cellular checkpoints have evolved to adjust the responses of mitochondria and synapses to the buildup of chronic stress. NR4A1 plays such a role by controlling the energetic competence of mitochondria with respect to synapse number. As an immediate-early gene, Nr4a1 promotes neuronal plasticity, but sustained expression or activity can be detrimental. NR4A1 expression and activity is sustained by chronic stress in animal models and in human studies of neuropathologies sensitive to the buildup of chronic stress. Therefore, antagonism of NR4A1 is a promising avenue for preventing the regressive synaptic reorganization in cortical systems in the context of chronic stress.

Decreased SGK1 Expression and Function Contributes to Behavioral Deficits Induced by Traumatic Stress.

Exposure to extreme stress can trigger the development of major depressive disorder (MDD) as well as post-traumatic stress disorder (PTSD). The molecular mechanisms underlying the structural and functional alterations within corticolimbic brain regions, including the prefrontal cortex (PFC) and amygdala of individuals subjected to traumatic stress, remain unknown. In this study, we show that serum and glucocorticoid regulated kinase 1 (SGK1) expression is down-regulated in the postmortem PFC of PTSD subjects. Furthermore, we demonstrate that inhibition of SGK1 in the rat medial PFC results in helplessness- and anhedonic-like behaviors in rodent models. These behavioral changes are accompanied by abnormal dendritic spine morphology and synaptic dysfunction. Together, the results are consistent with the possibility that altered SGK1 signaling contributes to the behavioral and morphological phenotypes associated with traumatic stress pathophysiology.

Cariprazine Exhibits Anxiolytic and Dopamine D3 Receptor-Dependent Antidepressant Effects in the Chronic Stress Model.

Background: Cariprazine, a D3-preferring dopamine D2/D3 receptor partial agonist, is a new antipsychotic drug recently approved in the United States for the treatment of schizophrenia and bipolar mania. We recently demonstrated that cariprazine also has significant antianhedonic-like effects in rats subjected to chronic stress; however, the exact mechanism of action for cariprazine's antidepressant-like properties is not known. Thus, in this study we examined whether the effects of cariprazine are mediated by dopamine D3 receptors. Methods: Wild-type and D3-knockout mice were exposed to chronic unpredictable stress for up to 26 days, treated daily with vehicle, imipramine (20 mg/kg), aripiprazole (1 and 5 mg/kg), or cariprazine (0.03, 0.1, 0.2, and 0.4 mg/kg), and tested in behavioral assays measuring anhedonia and anxiety-like behaviors. Results: Results showed that cariprazine significantly attenuated chronic unpredictable stress-induced anhedonic-like behavior in wild-type mice, demonstrating potent antidepressant-like effects comparable with aripiprazole and the tricyclic antidepressant imipramine. This antianhedonic-like effect of cariprazine was not observed in D3-knockout mice, suggesting that the cariprazine antidepressant-like activity is mediated by dopamine D3 receptors. Moreover, cariprazine significantly reduced drinking latency in the novelty-induced hypophagia test in wild-type mice, further confirming its antianhedonic-like effect and showing that it also has anxiolytic-like activity. Conclusions: In combination with previous studies, these results suggest that cariprazine has a unique pharmacological profile and distinct dopamine D3 receptor-dependent mechanism of action that may be beneficial in the treatment of schizophrenia, bipolar disorder, and major depressive disorder.

Kinase-mediated signaling cascades in mood disorders and antidepressant treatment.

Kinase-mediated signaling cascades regulate a number of different molecular mechanisms involved in cellular homeostasis, and are viewed as one of the most common intracellular processes that are robustly dysregulated in the pathophysiology of mood disorders such as depression. Newly emerged, rapid acting antidepressants are able to achieve therapeutic improvement, possibly in part, through stimulating activity of kinase-dependent signaling pathways. Thus, advancements in our understanding of how kinases may contribute to development and treatment of depression seem crucial. However, current investigations are limited to a single or small number of kinases and are unable to detect novel kinases. Here, we review fast developing kinome profiling approaches that allow identification of multiple kinases and kinase network connections simultaneously, analyze technical limitation and challenges, and discuss their future applications to mood disorders and antidepressant treatment.

Comorbidity Factors and Brain Mechanisms Linking Chronic Stress and Systemic Illness.

Neuropsychiatric symptoms and mental illness are commonly present in patients with chronic systemic diseases. Mood disorders, such as depression, are present in up to 50% of these patients, resulting in impaired physical recovery and more intricate treatment regimen. Stress associated with both physical and emotional aspects of systemic illness is thought to elicit detrimental effects to initiate comorbid mental disorders. However, clinical reports also indicate that the relationship between systemic and psychiatric illnesses is bidirectional, further increasing the complexity of the underlying pathophysiological processes. In this review, we discuss the recent evidence linking chronic stress and systemic illness, such as activation of the immune response system and release of common proinflammatory mediators. Altogether, discovery of new targets is needed for development of better treatments for stress-related psychiatric illnesses as well as improvement of mental health aspects of different systemic diseases.

Depression and treatment response: dynamic interplay of signaling pathways and altered neural processes.

Since the 1960s, when the first tricyclic and monoamine oxidase inhibitor antidepressant drugs were introduced, most of the ensuing agents were designed to target similar brain pathways that elevate serotonin and/or norepinephrine signaling. Fifty years later, the main goal of the current depression research is to develop faster-acting, more effective therapeutic agents with fewer side effects, as currently available antidepressants are plagued by delayed therapeutic onset and low response rates. Clinical and basic science research studies have made significant progress towards deciphering the pathophysiological events within the brain involved in development, maintenance, and treatment of major depressive disorder. Imaging and postmortem brain studies in depressed human subjects, in combination with animal behavioral models of depression, have identified a number of different cellular events, intracellular signaling pathways, proteins, and target genes that are modulated by stress and are potentially vital mediators of antidepressant action. In this review, we focus on several neural mechanisms, primarily within the hippocampus and prefrontal cortex, which have recently been implicated in depression and treatment response.

Case report: Unilateral paralysis of the hypoglossal nerve as the only clinical sign of clivus meningioma - a case report and literature review.

Introduction: Clivus meningiomas are benign tumors that occur at the skull base in the posterior cranial fossa. Symptoms usually progress several months or years before diagnosis and may include: headache, vertigo, hearing impairment, ataxia with gait disturbances, sensory problems. In the neurological findings, paralysis of the lower cranial nerves is most often seen, which in the later course can be accompanied by cerebellar and pyramidal signs until the development of a consciousness impairment. Case presentation: We presented the case of a patient who at the time of diagnosis had only unilateral hypoglossal nerve paralysis with dysarthria and mild dysphagia. After the neurosurgical procedure, pathohistological analysis confirmed meningothelial meningioma. Conclusion: Early recognition of clivus tumors, which include meningiomas, is necessary in order to implement an adequate therapeutic procedure and prevent further deterioration of the patient's condition.

Novel hippocampal genes involved in enhanced susceptibility to chronic pain-induced behavioral emotionality.

Altered mood and psychiatric disorders are commonly associated with chronic pain conditions; however, brain mechanisms linking pain and comorbid clinical depression are still largely unknown. In this study, we aimed to identify whether key genes/cellular mechanisms underlie susceptibility/resiliency to development of depressive-like behaviors during chronic pain state. Genome-wide RNA-seq analysis was used to examine the transcriptomic profile of the hippocampus, a limbic brain region that regulates mood and stress responses, from male rats exposed to chronic inflammatory pain. Pain-exposed animals were separated into either 'resilient' or 'susceptible' to development of enhanced behavioral emotionality based on behavioral testing. RNA-seq bioinformatic analysis, followed by validation using qPCR, revealed dysregulation of hippocampal genes involved in neuroinflammation, cell cycle/neurogenesis and blood-brain barrier integrity. Specifically, ADAM Metallopeptidase Domain 8 (Adam8) and Aurora Kinase B (Aurkb), genes with functional roles in activation of the NLRP3 inflammasome and microgliosis, respectively, were significantly upregulated in the hippocampus of 'susceptible' animals expressing increased behavioral emotionality. In addition, genes associated with blood-brain barrier integrity, such as the Claudin 4 (Cldn4), a tight junction protein and a known marker of astrocyte activation, were also significantly dysregulated between 'resilient' or 'susceptible' pain groups. Furthermore, differentially expressed genes (DEGs) were further characterized in rodents stress models to determine whether their hippocampal dysregulation is driven by common stress responses vs. affective pain processing. Altogether these results continue to strengthen the connection between dysregulation of hippocampal genes involved in neuroinflammatory and neurodegenerative processes with increased behavioral emotionality often expressed in chronic pain state.

Altered expression of synapse and glutamate related genes in post-mortem hippocampus of depressed subjects.

Major depressive disorder (MDD) has been linked to changes in function and activity of the hippocampus, one of the central limbic regions involved in regulation of emotions and mood. The exact cellular and molecular mechanisms underlying hippocampal plasticity in response to stress are yet to be fully characterized. In this study, we examined the genetic profile of micro-dissected subfields of post-mortem hippocampus from subjects diagnosed with MDD and comparison subjects matched for sex, race and age. Gene expression profiles of the dentate gyrus and CA1 were assessed by 48K human HEEBO whole genome microarrays and a subgroup of identified genes was confirmed by real-time polymerase chain reaction (qPCR). Pathway analysis revealed altered expression of several gene families, including cytoskeletal proteins involved in rearrangement of neuronal processes. Based on this and evidence of hippocampal neuronal atrophy in MDD, we focused on the expression of cytoskeletal, synaptic and glutamate receptor genes. Our findings demonstrate significant dysregulation of synaptic function/structure related genes SNAP25, DLG2 (SAP93), and MAP1A, and 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid receptor subunit genes GLUR1 and GLUR3. Several of these human target genes were similarly dysregulated in a rat model of chronic unpredictable stress and the effects reversed by antidepressant treatment. Together, these studies provide new evidence that disruption of synaptic and glutamatergic signalling pathways contribute to the pathophysiology underlying MDD and provide interesting targets for novel therapeutic interventions.

Hippocampal mitogen-activated protein kinase phosphatase-1 regulates behavioral and systemic effects of chronic corticosterone administration.

Clinical reports indicate a bidirectional relationship between mental illness and chronic systemic diseases. However, brain mechanisms linking chronic stress and development of mood disorders to accompanying peripheral organ dysfunction are still not well characterized in animal models. In the current study, we investigated whether activation of hippocampal mitogen-activated protein kinase phosphatase-1 (MKP-1), a key factor in depression pathophysiology, also acts as a mediator of systemic effects of stress. First, we demonstrated that treatment with the glucocorticoid receptor (GR) agonist dexamethasone or acute restraint stress (ARS) significantly increased Mkp-1 mRNA levels within the rat hippocampus. Conversely, administration of the GR antagonist mifepristone 30 min before ARS produced a partial blockade of Mkp-1 upregulation, suggesting that stress activates MKP-1, at least in part, through upstream GR signaling. Chronic corticosterone (CORT) administration evoked comparable increases in hippocampal MKP-1 protein levels and produced a robust increase in behavioral emotionality. In addition to behavioral deficits, chronic CORT treatment also produced systemic pathophysiological effects. Elevated levels of renal inflammation protein markers (NGAL and IL18) were observed suggesting tissue damage and early kidney impairment. In a rescue experiment, the effects of CORT on development of depressive-like behaviors and increased NGAL and IL18 protein levels in the kidney were blocked by CRISPR-mediated knockdown of hippocampal Mkp-1 prior to CORT exposure. In sum, these findings further demonstrate that MKP-1 is necessary for development of enhanced behavioral emotionality, while also suggesting a role in stress mechanisms linking brain dysfunction and systemic illness such as kidney disease.

Corticosterone as a Potential Confounding Factor in Delineating Mechanisms Underlying Ketamine's Rapid Antidepressant Actions.

Recent research into the rapid antidepressant effect of subanesthetic doses of ketamine have identified a series of relevant protein cascades activated within hours of administration. Prior to, or concurrent with, these activation cascades, ketamine treatment generates dissociative and psychotomimetic side effects along with an increase in circulating glucocorticoids. In rats, we observed an over 3-fold increase in corticosterone levels in both serum and brain tissue, within an hour of administration of low dose ketamine (10 mg/kg), but not with (2R, 6R)-hydroxynorketamine (HNK) (10 mg/kg), a ketamine metabolite shown to produce antidepressant-like action in rodents without inducing immediate side-effects. Hippocampal tissue from ketamine, but not HNK, injected animals displayed a significant increase in the expression of sgk1, a downstream effector of glucocorticoid receptor signaling. To examine the role conscious sensation of ketamine's side effects plays in the release of corticosterone, we assessed serum corticosterone levels after ketamine administration while under isoflurane anesthesia. Under anesthesia, ketamine failed to increase circulating corticosterone levels relative to saline controls. Concurrent with its antidepressant effects, ketamine generates a release of glucocorticoids potentially linked to disturbing cognitive side effects and the activation of distinct molecular pathways which should be considered when attempting to delineate the molecular mechanisms of its antidepressant function.

An additional motor-related field in the lateral frontal cortex of squirrel monkeys.

Our earlier efforts to document the cortical connections of the ventral premotor cortex (PMv) revealed dense connections with a field rostral and lateral to PMv, an area we called the frontal rostral field (FR). Here, we present data collected in FR using electrophysiological and anatomical methods. Results show that FR contains an isolated motor representation of the forelimb that can be differentiated from PMv based on current thresholds and latencies to evoke electromyographic activity using intracortical microstimulation techniques. In addition, FR has a different pattern of cortical connections compared with PMv. Together, these data support that FR is an additional, previously undescribed motor-related area in squirrel monkeys.

Neurokinin-1 (NK-1) receptor and brain-derived neurotrophic factor (BDNF) gene expression is differentially modulated in the rat spinal dorsal horn and hippocampus during inflammatory pain.

Persistent pain produces complex alterations in sensory pathways of the central nervous system (CNS) through activation of various nociceptive mechanisms. However, the effects of pain on higher brain centers, particularly the influence of the stressful component of pain on the limbic system, are poorly understood. Neurokinin-1 (NK-1) receptors and brain-derived neurotrophic factor (BDNF), known neuromediators of hyperalgesia and spinal central sensitization, have also been implicated in the plasticity and neurodegeneration occurring in the hippocampal formation during exposures to various stressors. Results of this study showed that injections of complete Freund's adjuvant (CFA) into the hind paw increased NK-1 receptor and BDNF mRNA levels in the ipsilateral dorsal horn, supporting an important role for these nociceptive mediators in the amplification of ascending pain signaling. An opposite effect was observed in the hippocampus, where CFA down-regulated NK-1 receptor and BDNF gene expression, phenomena previously observed in immobilization models of stress and depression. Western blot analyses demonstrated that in the spinal cord, CFA also increased levels of phosphorylated cAMP response element-binding protein (CREB), while in the hippocampus the activation of this transcription factor was significantly reduced, further suggesting that tissue specific transcription of either NK-1 or BDNF genes may be partially regulated by common intracellular transduction mechanisms mediated through activation of CREB. These findings suggest that persistent nociception induces differential regional regulation of NK-1 receptor and BDNF gene expression and CREB activation in the CNS, potentially reflecting varied roles of these neuromodulators in the spinal cord during persistent sensory activation vs. modulation of the higher brain structures such as the hippocampus.

Characterization of GABAergic marker expression in the chronic unpredictable stress model of depression.

Evidence continues to build suggesting that the GABAergic neurotransmitter system is altered in brains of patients with major depressive disorder. However, there is little information available related to the extent of these changes or the potential mechanisms associated with these alterations. As stress is a well-established precipitant to depressive episodes, we sought to explore the impact of chronic stress on GABAergic interneurons. Using western blot analyses and quantitative real-time PCR (qPCR) we assessed the effects of five-weeks of chronic unpredictable stress (CUS) exposure on the expression of GABA-synthesizing enzymes (GAD65 and GAD67), calcium-binding proteins (calbindin (CB), parvalbumin (PV) and calretinin (CR)), and neuropeptides co-expressed in GABAergic neurons (somatostatin (SST), neuropeptide Y (NPY), vasoactive intestinal peptide (VIP) and cholecystokinin (CCK)) in the prefrontal cortex (PFC) and hippocampus (HPC) of rats. We also investigated the effects of corticosterone (CORT) and dexamethasone (DEX) exposure on these markers in vitro in primary cortical and hippocampal cultures. We found that CUS induced significant reductions of GAD67 protein levels in both the PFC and HPC of CUS-exposed rats, but did not detect changes in GAD65 protein expression. Similar protein expression changes were found in vitro in cortical neurons. In addition, our results provide clear evidence of reduced markers of interneuron population(s), namely SST and NPY, in the PFC, suggesting these cell types may be selectively vulnerable to chronic stress. Together, this work highlights that chronic stress induces regional and cell type-selective effects on GABAergic interneurons in rats. These findings provide additional supporting evidence that stress-induced GABA neuron dysfunction and cell vulnerability play critical roles in the pathophysiology of stress-related illnesses, including major depressive disorder.

GABA(B) receptor function and subunit expression in the rat spinal cord as indicators of stress and the antinociceptive response to antidepressants.

Experiments were undertaken to examine whether once daily i.p. administration of either of two antidepressants used for the treatment of neuropathic pain, amitriptyline (10 mg/kg) and fluoxetine (5 mg/kg), to rats for 7 days modifies GABA(B) receptor function and subunit expression in the lumbar spinal cord. The results indicate that, as previously reported for desipramine, both amitriptyline and fluoxetine increase the pain threshold to a thermal stimulus, the expression of GABA(B(1)) subunits, and baclofen-stimulated [35S]GTPgammaS binding, a measure of GABA(B) receptor function. The effects of antidepressant administration on GABA(B(1b)) and GABA(B(2)) subunit expression in spinal cord are more variable than for GABA(B(1a)). It was also discovered that repeated daily exposure to a thermal stimulus or immobilization stress increases GABA(B(1a)) expression in the lumbar spinal cord, with no commensurate change in thermal pain threshold or GABA(B) receptor sensitivity. These results support a relationship between GABA(B) receptors and the action of antidepressants. The findings demonstrate that drug-induced increases in GABA(B) receptor function can occur independently of any change in GABA(B) receptor subunit expression and are consistent with the notion that GABA(B) receptor subunits have multiple functions, only one of which is dimerization to form GABA(B) receptors. The data also suggest that GABA(B) subunit gene expression may serve as a preclinical marker of antidepressant efficacy and of drug- or stress-induced modifications in central nervous system activity.

Persistent pain produces stress-like alterations in hippocampal neurogenesis and gene expression.

UNLABELLED: Clinical observations have shown that patients with chronic pain are often depressed, suggesting the importance of the affective or emotional component of pain and its impact on cognition. In this study we investigated pain-induced activation of the hippocampus to address possible molecular and cellular events that may underlie the comorbidity of chronic pain and depression. Rats received either an acute (formalin) or chronic (complete Freund's adjuvant) inflammatory stimulus to the hind paw or an acute or chronic immobilization. Results demonstrated that pain can alter hippocampal morphology and gene expression. Bromodeoxyuridine (BrdU) staining indicated that neurogenesis in the hippocampal dentate gyrus was significantly reduced after long-term inflammatory nociception, similar to previous observations after various stress models. Important activators of nociception-induced spinal central sensitization, the neurokinin-1 (NK-1) receptor and brain-derived neurotrophic factor (BDNF), have also been intimately associated with depressive processes in the limbic system. In situ hybridization assay results demonstrated that either pain or stress (acute or chronic treatments) reduced the levels of both NK-1 receptor and BDNF mRNAs in the cornu ammonis 1-3 sublayers of the hippocampus, suggesting a possible role of these neuromediators in processing of pain in higher brain centers. PERSPECTIVE: The findings in this study demonstrate that persistent pain induces stress-like damaging modulatory effects in the hippocampus, which is one of the limbic regions involved in the pathophysiology of depression. Targeting these mechanisms (which are potential contributors to the emotional impact of pain) may provide novel therapeutic approaches for relieving depression-like aspects of chronic pain.

Psychological Stress Activates the Inflammasome via Release of Adenosine Triphosphate and Stimulation of the Purinergic Type 2X7 Receptor.

BACKGROUND: The mechanisms underlying stress-induced inflammation that contribute to major depressive disorder are unknown. We examine the role of the adenosine triphosphate (ATP)/purinergic type 2X7 receptor (P2X7R) pathway and the NLRP3 (nucleotide-binding, leucine-rich repeat, pyrin domain containing 3) inflammasome in interleukin (IL)-1ß and depressive behavioral responses to stress. METHODS: The influence of acute restraint stress on extracellular ATP, glutamate, IL-1ß, and tumor necrosis factor alpha in hippocampus was determined by microdialysis, and the influence of acute restraint stress on the NLRP3 inflammasome was determined by western blot analysis. The influence of P2X7R antagonist administration on IL-1ß and tumor necrosis factor alpha and on anxiety and depressive behaviors was determined in the chronic unpredictable stress rodent model. The role of the NLRP3 inflammasome was determined by analysis of Nlrp3 null mice. RESULTS: Acute restraint stress rapidly increased extracellular ATP, an endogenous agonist of P2X7R; the inflammatory cytokine IL-1ß; and the active form of the NLRP3 inflammasome in the hippocampus. Administration of a P2X7R antagonist completely blocked the release of IL-1ß and tumor necrosis factor alpha, another stress-induced cytokine, and activated NLRP3. Moreover, P2X7R antagonist administration reversed the anhedonic and anxiety behaviors caused by chronic unpredictable stress exposure, and deletion of the Nlrp3 gene rendered mice resistant to development of depressive behaviors caused by chronic unpredictable stress. CONCLUSIONS: These findings demonstrate that psychological "stress" is sensed by the innate immune system in the brain via the ATP/P2X7R-NLRP3 inflammasome cascade, and they identify novel therapeutic targets for the treatment of stress-related mood disorders and comorbid illnesses.

REDD1 is essential for stress-induced synaptic loss and depressive behavior.

Major depressive disorder (MDD) affects up to 17% of the population, causing profound personal suffering and economic loss. Clinical and preclinical studies have revealed that prolonged stress and MDD are associated with neuronal atrophy of cortical and limbic brain regions, but the molecular mechanisms underlying these morphological alterations have not yet been identified. Here, we show that stress increases levels of REDD1 (regulated in development and DNA damage responses-1), an inhibitor of mTORC1 (mammalian target of rapamycin complex-1; ref. 10), in rat prefrontal cortex (PFC). This is concurrent with a decrease in phosphorylation of signaling targets of mTORC1, which is implicated in protein synthesis-dependent synaptic plasticity. We also found that REDD1 levels are increased in the postmortem PFC of human subjects with MDD relative to matched controls. Mutant mice with a deletion of the gene encoding REDD1 are resilient to the behavioral, synaptic and mTORC1 signaling deficits caused by chronic unpredictable stress, whereas viral-mediated overexpression of REDD1 in rat PFC is sufficient to cause anxiety- and depressive-like behaviors and neuronal atrophy. Taken together, these postmortem and preclinical findings identify REDD1 as a critical mediator of the atrophy of neurons and depressive behavior caused by chronic stress exposure.

Antidepressant effects of fibroblast growth factor-2 in behavioral and cellular models of depression.

BACKGROUND: Basic and clinical studies report that the expression of fibroblast growth factor-2 (FGF-2) is decreased in the prefrontal cortex (PFC) of depressed subjects or rodents exposed to stress and increased following antidepressant treatment. Here, we aim to determine if 1) FGF-2/fibroblast growth factor receptor (FGFR) signaling is sufficient and required for mediating an antidepressant response behaviorally and cellularly; and 2) if the antidepressant actions of FGF-2 are mediated specifically by the PFC. METHODS: The role of FGF-2 signaling in behavioral models of depression and anxiety was tested using chronic unpredictable stress (CUS)/sucrose consumption test (SCT), forced swim test (FST), and novelty suppressed feeding test (NSFT). We also assessed the number of bromodeoxyuridine labeled dividing glial cells in the PFC as a cellular index relevant to depression (i.e., decreased by stress and increased by antidepressant treatment). RESULTS: Chronic FGF-2 infusions (intracerebroventricular) blocked the deficit in SCT caused by CUS. Moreover, the response to antidepressant treatment in the CUS/SCT and FST was abolished upon administration of an inhibitor of FGFR activity, SU5402. These results are consistent with the regulation of proliferating cells in the PFC, a portion of which are of oligodendrocyte lineage. Lastly, subchronic infusions of FGF-2 into the PFC but not into the dorsal striatum produced antidepressant-like and anxiolytic-like effects on FST and NSFT respectively. CONCLUSIONS: These findings demonstrate that FGF-2/FGFR signaling is sufficient and necessary for the behavioral, as well as gliogenic, actions of antidepressants and highlight the PFC as a brain region sensitive to the antidepressant actions of FGF-2.

Signaling pathways underlying the rapid antidepressant actions of ketamine.

Currently available medications have significant limitations, most notably low response rate and time lag for treatment response. Recent clinical studies have demonstrated that ketamine, an NMDA receptor antagonist produces a rapid antidepressant response (within hours) and is effective in treatment resistant depressed patients. Molecular and cellular studies in rodent models demonstrate that ketamine rapidly increases synaptogenesis, including increased density and function of spine synapses, in the prefrontal cortex (PFC). Ketamine also produces rapid antidepressant actions in behavioral models of depression, and reverses the deficits in synapse number and behavior resulting from chronic stress exposure. These effects of ketamine are accompanied by stimulation of the mammalian target of rapamycin (mTOR), and increased levels of synaptic proteins. Together these studies indicate that ketamine rapidly reverses the atrophy of spines in the PFC and thereby causes a functional reconnection of neurons that underlies the rapid behavioral responses. These findings identify new targets for rapid acting antidepressants that are safer than ketamine. This article is part of a Special Issue entitled 'Anxiety and Depression'.