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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.

Although ketamine represents a new line of antidepressants with unique clinical advantages, its use as a long-term treatment has limitations, particularly its dissociative/psychotomimetic effects and abuse potential. In rats, we observed that a subanesthetic dose of ketamine (10mg/kg) induced a 3-fold increase in corticosterone (CORT) levels in both serum and brain tissue, within an hour of administration. This increase took place in both male and female rats, in both naïve and stressed animals. However, no CORT increase was detected in rats injected with (2R, 6R)-hydroxynorketamine (HNK), an active metabolite of ketamine, that is believed to contribute to ketamine’s antidepressant effect. In response to the release in CORT, ketamine injected animals displayed a significant increase in the expression of sgk1, a downstream effector of glucocorticoid receptor signaling, in the hippocampus indicating the initiation of a transcriptional program. We hypothesized this surge in CORT release was a manifestation of stress experienced by the rat in response to ketamine’s psychotropic effects. When sensory perception was blocked under isoflurane anesthesia, administration of ketamine did not increase circulating CORT levels as compared to animals injected with saline. Taken together, ketamine administration triggers a behavioral stress response that has downstream molecular consequences. The resulting CORT release, virtually concurrent with the timing of ketamine’s rapid-acting antidepressant actions, necessitates the consideration of this pathway’s potential involvement when trying to dissect out the relevant molecular mechanisms underlying ketamine’s action.

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)-1β and depressive behavioral responses to stress. Methods The influence of acute restraint stress on extracellular ATP, glutamate, IL-1β, 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-1β 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-1β; and the active form of the NLRP3 inflammasome in the hippocampus. Administration of a P2X7R antagonist completely blocked the release of IL-1β 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.

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.

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.

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.

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.

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.

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.

The lifetime prevalence (~16%) 1 and the economic burden ($100 billion annually) 2,3 associated with major depressive disorder (MDD) make it one of the most common and debilitating neurobiological illnesses. To date, the exact cellular and molecular mechanisms underlying the pathophysiology of MDD have not been identified. Here we use whole-genome expression profiling of postmortem tissue and show significantly increased expression of mitogenactivated protein kinase (MAPK) phosphatase-1 (MKP-1, encoded by DUSP1, but hereafter called MKP-1) in the hippocampal subfields of subjects with MDD compared to matched controls. MKP-1, also known as dual-specificity phosphatase-1 (DUSP1), is a member of a family of proteins that dephosphorylate both threonine and tyrosine residues and thereby serves as a key negative regulator of the MAPK cascade 4 , a major signaling pathway involved in neuronal plasticity, function and survival 5,6 . We tested the role of altered MKP-1 expression in rat and mouse models of depression and found that increased hippocampal MKP-1 expression, as a result of stress or viral-mediated gene transfer, causes depressive behaviors. Conversely, chronic antidepressant treatment normalizes stress-induced MKP-1 expression and behavior, and mice lacking MKP-1 are resilient to stress. These postmortem and preclinical studies identify MKP-1 as a key factor in MDD pathophysiology and as a new target for therapeutic interventions. Brain imaging and postmortem studies have provided evidence of changes in the cellular architecture of several limbic brain regions, most notably atrophy of hippocampal pyramidal neurons and a correspond-­ing reduction in the volume of this region, in individuals with MDD 7–10 . Preclinical studies also show that stress causes atrophy of the apical den-­drites of pyramidal neurons and decreases neurogenesis in the dentate gyrus of the adult hippocampus 11–13 . Such alterations of the structure and function of the hippocampus could contribute to certain aspects of MDD, including disruption of cognition, depressed mood, helplessness, anhedonia and control of the hypothalamic-­pituitary -­ adrenal axis 14–18 .

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.

Clinical studies show that people suffering from chronic pain are often also burdened by depression. Antidepressants are used to treat some types of chronic pain; however, little is known about their mechanisms of action. This study addressed the effects of a nonsteroidal anti-inflammatory drug and a tricyclic antidepressant drug on pain- and stress-evoked gene expression in the rat spinal cord dorsal horn and hippocampus. Rats were pretreated with either indomethacin or imipramine and then challenged with either intraplantar complete Freund's adjuvant or a bout of immobilization stress. Results showed that indomethacin significantly reduced nociception-related peripheral edema, hyperalgesia, and reversed the pain-evoked up-regulation of neurokinin (NK)-1 receptor and brain-derived neurotrophic factor (BDNF) gene expression in the spinal cord to levels not statistically different from controls. However, indomethacin did not protect against significant pain-induced down-regulation of these genes in the hippocampus by approximately 50%, suggesting that although analgesic drug treatment reduces nociceptive sensory activation in the spinal cord, it is insufficient to prevent the impact of pain on the hippocampus. Conversely, although imipramine did not provide significant behavioral analgesia, it significantly blocked both pain- and stress-evoked alterations in hippocampal and spinal NK-1 and BDNF gene expression. Thus, these results show that application of either analgesic or antidepressant drugs alone does not fully protect against both the behavioral and molecular effects of persistent pain on both "sensory" and "affective" processing within the central nervous system.

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.

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.

Background 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. Methods Using western blot analyses and quantitative real-time polymerase chain reaction, we assessed the effects of five-weeks of chronic unpredictable stress exposure on the expression of GABA-synthesizing enzymes (GAD65 and GAD67), calcium-binding proteins (calbindin, parvalbumin, and calretinin), and neuropeptides co-expressed in GABAergic neurons (somatostatin, neuropeptide Y, vasoactive intestinal peptide, and cholecystokinin) in the prefrontal cortex and hippocampus of rats. We also investigated the effects of corticosterone and dexamethasone exposure on these markers in vitro in primary cortical and hippocampal cultures. Results We found that chronic unpredictable stress induced significant reductions of GAD67 protein levels in both the prefrontal cortex and hippocampus of chronic unpredictable stress-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 somatostatin and neuropeptide Y, in the prefrontal cortex, suggesting these cell types may be selectively vulnerable to chronic stress. Conclusion 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.

For several decades the medical science society has been in dilemma and debating about when a person is actually considered dead. That a person is dead when his/her brain dies is the attitude of not only medical science, but culture as a whole 1, . The notion that took years to establish of heart being not only the “primum movens” but also the “ultimum morines”, that is that life begins with a heart beat and ends with its arrest, has been abandoned in the last 30 years. From a biological standpoint dying does not recognize the border between the death of the heart and the death of the brain. At the moment of termination of brain function breathing stops as well, and a few minutes or days after, heart failure occurs. The concept of brain death as the death of an individual, has brought forward many philosophical, ethical, medical, legal and economic issues, and created a dilemma as to when a person is considered dead, from the first report of Mollaret and Goulon in 1959, as a “coma depasse” . Soon after that the Harvard Medical School (Harvard criteria of 1968) 1 was the first one to define brain death as an “irreversible coma” which includes the lack of consciousness, spontaneous movement and all reflexes. Since then, the definition and diagnostic criteria have been subjected to significant changes and most of the problems, dilemmas and debates which had before been caused by the concept of brain death due to terminological confusion and great responsibility to declare someone dead with the preserved cardiac function, have been overcome. However, although brain death is now accepted worldwide, diagnosis and diagnostic criteria are far from perfect, therefore further adjustments are needed. The diagnosis of brain death

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'.

Background Despite recent interest in glycogen synthase kinase-3β (GSK-3β) as a target for the treatment of mood disorders, there has been very little work related to these illnesses on the upstream signaling molecules that regulate this kinase as well as downstream targets. Methods With a focused microarray approach we examined the influence of different classes of antidepressants on Wnt signaling that controls GSK-3β activity as well as the transcription factors that contribute to the actions of GSK-3β. Results The results demonstrate that Wnt2 is a common target of different classes of antidepressants and also show differential regulation of Wnt-GSK-3β signaling genes. Increased expression and function of Wnt2 was confirmed by secondary measures. Moreover, with a viral vector approach we demonstrate that increased expression of Wnt2 in the hippocampus is sufficient to produce antidepressant-like behavioral actions in well-established models of depression and treatment response. Conclusions These findings demonstrate that Wnt2 expression and signaling is a common target of antidepressants and that increased Wnt2 is sufficient to produce antidepressant effects.

Acute or chronic stress can alter hippocampal structure, cause neuronal damage, and decrease hippocampal levels of the neurotrophin brain-derived neurotrophic factor (BDNF). The tachykinin substance P and its neurokinin-1 (NK-1) receptor may play a critical role in neuronal systems that process nociceptive stimuli; their importance in stress-activated systems has recently been demonstrated by the antidepressant-like actions of NK-1 receptor antagonists. However, the functional similarities between neurokinin receptors in the hippocampus and those in sensory systems are poorly understood, as is the significance of hippocampal NK-1 receptor in the context of chronic pain. Therefore, we investigated the effects of immobilization stress or inflammatory stimuli on NK-1 receptor and BDNF gene expression in the rat hippocampus. Rats received an acute or chronic immobilization stress, or an acute (formalin) or chronic (complete Freund's adjuvant) inflammatory stimulus to the right hind paw. Subsequently hippocampal volume and specific gravity were measured and NK-1 receptor and BDNF mRNA levels quantified using ribonuclease protection assays. Results showed that either stress or pain down-regulates expression of both NK-1 receptor and BDNF genes in the hippocampus. Hippocampal volume was increased by either pain or stress; this may be due to edema (decreased specific gravity). Thus, BDNF and NK-1 receptor gene plasticity may reflect sensory activation or responses to neuronal injury. These data may provide useful markers of hippocampal activation during chronic pain, and suggest similarities in the mechanisms underlying chronic pain and depression.

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.

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., Activity of the protein kinase SGK1 is reduced in the prefrontal cortex of individuals with post-traumatic stress disorder (PTSD), and SGK1 inhibition can cause PTSD-related behavioral changes in an animal model., Author Summary Improper functioning of the brain regions known as prefrontal cortex and amygdala is associated with the development of post-traumatic stress disorder. However, little is known about the molecular mechanisms that underlie this condition. We found that the expression of a protein kinase involved in cellular responses to stress, known as serum and glucocorticoid regulated kinase 1 (SGK1), was decreased in the prefrontal cortex of subjects who had died with post-traumatic stress disorder. Furthermore, we found that experimentally decreasing SGK1 function in the prefrontal cortex of rats resulted in behaviors characteristic of traumatic stress, including the unwillingness to avoid discomfort and the inability to experience pleasure. Finally, reduced SGK1 function in neurons affected their basic electrophysiological properties and caused a decrease in the number of dendritic spines—the specialized protrusions of dendrites that receive synaptic inputs.