Chronic social defeat up-regulates expression of norepinephrine transporter in rat brains.

Stress has been reported to activate the locus coeruleus (LC)-noradrenergic system. However, the molecular link between chronic stress and noradrenergic neurons remains to be elucidated. In the present study adult Fischer 344 rats were subjected to a regimen of chronic social defeat (CSD) for 4weeks. Measurements by in situ hybridization and Western blotting showed that CSD significantly increased mRNA and protein levels of the norepinephrine transporter (NET) in the LC region and NET protein levels in the hippocampus, frontal cortex and amygdala. CSD-induced increases in NET expression were abolished by adrenalectomy or treatment with corticosteroid receptor antagonists, suggesting the involvement of corticosterone and corticosteroid receptors in this upregulation. Furthermore, protein levels of protein kinase A (PKA), protein kinase C (PKC), and phosphorylated cAMP-response element binding (pCREB) protein were significantly reduced in the LC and its terminal regions by the CSD paradigm. Similarly, these reduced protein levels caused by CSD were prevented by adrenalectomy. However, effects of corticosteroid receptor antagonists on CSD-induced down-regulation of PKA, PKC, and pCREB proteins were not consistent. While mifeprestone and spironolactone, either alone or in combination, totally abrogate CSD effects on these protein levels of PKA, PKC and pCREB in the LC and those in the hippocampus, frontal cortex and amygdala, their effects on PKA and PKC in the hippocampus, frontal cortex and amygdala were region-dependent. The present findings indicate a correlation between chronic stress and activation of the noradrenergic system. This correlation and CSD-induced alteration in signal transduction molecules may account for their critical effects on the development of symptoms of major depression.

Does Alzheimer's disease result from attempts at repair or protection after transient stress?

This review explores the data indicating that the initial production of amyloid-beta precursor protein and phosphorylated tau are associated with physiological mechanisms for repair or protection of neurons exposed to significant disturbances in homeostasis. Stimuli as diverse as head injury, inhaled anesthetic agents, stimulant drugs, and both physiological (restraint) and psychological stress (social isolation) have been shown to increase brain expression of amyloid-beta and hyperphosphorylated tau without accompanying neurodegeneration. This review aims to encompass these responses as indicators of normal physiological processes that, in the case of Alzheimer's disease, are either unable to successfully repair or protect vulnerable neuronal populations from eventual neurodegeneration, but that are necessary components of an integrated nervous system that would be more susceptible to pathology if such processes were blocked in an attempt to minimize or prevent future damage.

Repeated immobilization stress alters rat hippocampal and prefrontal cortical morphology in parallel with endogenous agmatine and arginine decarboxylase levels.

Agmatine, an endogenous amine derived from decarboxylation of L-arginine catalyzed by arginine decarboxylase, has been proposed as a neurotransmitter or neuromodulator in the brain. In the present study, we examined whether agmatine has neuroprotective effects against repeated immobilization-induced morphological changes in brain tissues and possible effects of immobilization stress on endogenous agmatine levels and arginine decarboxylase expression in rat brains. Sprague-Dawley rats were subjected to 2h immobilization stress daily for 7 days. This paradigm significantly increased plasma corticosterone levels, and the glutamate efflux in the hippocampus as measured by in vivo microdialysis. Immunohistochemical staining with beta-tubulin III showed that repeated immobilization caused marked morphological alterations in the hippocampus and medial prefrontal cortex that were prevented by simultaneous treatment with agmatine (50mg/kg/day), i.p.). Likewise, endogenous agmatine levels measured by high-performance liquid chromatography in the prefrontal cortex, hippocampus, striatum and hypothalamus were significantly increased by immobilization, as compared to controls. The increased endogenous agmatine levels, ranging from 92 to 265% of controls, were accompanied by a significant increase of arginine decarboxylase protein levels in the same regions. These results demonstrate that the administration of exogenous agmatine protects the hippocampus and medial prefrontal cortex against neuronal insults caused by repeated immobilization. The parallel increase in endogenous brain agmatine and arginine decarboxylase protein levels triggered by repeated immobilization indicates that the endogenous agmatine system may play an important role in adaptation to stress as a potential neuronal self-protection mechanism.

Longitudinal brain corticotropin releasing factor and somatostatin in a transgenic mouse (TG2576) model of Alzheimer's disease.

Neuropeptides corticotropin releasing factor (CRF) and somatostatin (SRIF) are substantially decreased in cortical regions of Alzheimer's disease (AD) post-mortem brain tissue. The accumulation of amyloid-beta (Abeta) in AD brain has been postulated to be neurotoxic. Using male Tg2576 mice transgenic over-expressing amyloid-beta protein precursor (APP), we examined brain concentrations of CRF and SRIF at 12, 18 and 24 months. Mice were evaluated for locomotor activity and spatial memory. The APP mice had continued increased locomotor activity from 6 months of age compared to controls. Spatial memory was impaired beginning at 12 months in the APP mice relative to controls. APP mice at 24 months had a significantly higher number of amyloid plaques when compared to the 12 and 18 month time points. Brain concentrations of SRIF and CRF were significantly altered in a number of cortical and sub-cortical brain regions relative to controls, but in most regions were increased rather than decreased as in clinical AD. This data shows that although the insertion of the APP gene does cause age dependent increase in plaque load, it does not cause a change in regional neuropeptides consistent with AD, suggesting that neuropeptide changes in AD are not solely due to Abeta load.

Rapid eye movement sleep deprivation revives a form of developmentally regulated synaptic plasticity in the visual cortex of post-critical period rats.

The critical period for observing a developmentally regulated form of synaptic plasticity in the visual cortex of young rats normally ends at about postnatal day 30. This developmentally regulated form of in vitro long-term potentiation (LTP) can be reliably induced in layers II-III by aiming high frequency, theta burst stimulation (TBS) at the white matter situated directly below visual cortex (LTPWM-III). Previous work has demonstrated that suppression of sensory activation of visual cortex, achieved by rearing young rats in total darkness from birth, delays termination of the critical period for inducing LTPWM-III. Subsequent data also demonstrated that when rapid eye movement sleep (REMS) is suppressed, thereby reducing REMS cortical activation, just prior to the end of the critical period, termination of this developmental phase is delayed, and LTPWM-III can still be reliably produced in the usual post-critical period. Here, we report that for approximately 3 weeks immediately following the usual end of the critical period, suppression of REMS disrupts the maturational processes that close the critical period, and LTPWM-III is readily induced in brain slices taken from these somewhat older animals. Insofar as in vitro LTP is a model for the cellular and molecular changes that underlie developmental synaptic plasticity, these results suggest that mechanisms of synaptic plasticity, which participate in brain development and perhaps also in learning and memory processes, remain susceptible to the effects of REMS deprivation during the general period of adolescence in the rat.

Rapid eye movement sleep deprivation in post-critical period, adolescent rats alters the balance between inhibitory and excitatory mechanisms in visual cortex.

Suppression of rapid eye movement sleep (REMS) in developing animals has both anatomical and physiological consequences. We have recently shown that initiating REMS deprivation (REMSD) prior to the end of the critical period in young rats delays termination of the critical period (CP) in visual cortex, and, consequently, the synaptic plasticity mechanisms that support a developmentally regulated form of long-term potentiation (LTP) are maintained in an immature state [J.P. Shaffery, C.M. Sinton, G. Bisset, H.P. Roffwarg, G.A. Marks, Rapid eye movement sleep deprivation modifies expression of long-term potentiation in visual cortex of immature rats, Neuroscience, 110 (2002) 431-443]. In CP animals, high-frequency, theta burst stimulation (TBS) directed at the white matter (WM) below visual cortex produces LTP in the post-synaptic cells in layer II/III (LTPWM-III). However, LTPWM-III can be induced in cortical tissue taken from REMS-deprived animals for up to a week beyond the usual end of the CP [J.P. Shaffery, C.M. Sinton, G. Bisset, H.P. Roffwarg, G.A. Marks, Rapid eye movement sleep deprivation modifies expression of long-term potentiation in visual cortex of immature rats, Neuroscience, 110 (2002) 431-443]. Further, in post-CP, adolescent animals (as late as postnatal day 60), REMSD appears to unmask synaptic plasticity mechanisms that allow for production of developmentally regulated LTPWM-III [J.P. Shaffery, J. Lopez, G. Bissette, H.P. Roffwarg, Rapid eye movement sleep deprivation revives a form of developmentally regulated synaptic plasticity in the visual cortex of post-critical period rats, Neurosci Lett., (2005), in press]. It has been proposed that REMSD's effects on production of LTPWM-III result from a reduction in efficiency of the inhibitory mechanisms thought to precipitate termination of the CP of brain development [J.P. Shaffery, J. Lopez, G. Bissette, H.P. Roffwarg, Rapid eye movement sleep deprivation revives a form of developmentally regulated synaptic plasticity in the visual cortex of post-critical period rats, Neurosci Lett., (2005), in press]. In this study we tested the hypothesis that low-frequency stimulation (LFS) of the fibers of the WM, which usually produces the related form of synaptic plasticity, long-term depression (LTD), will also reflect the reduction in inhibitory tone. We report here that LFS protocols, which in normally sleeping, adolescent rats usually produce either LTD or no change in response magnitude, in REMS-deprived, adolescent rats are more likely to produce LTP.

Omega-3 status and cerebrospinal fluid corticotrophin releasing hormone in perpetrators of domestic violence.

BACKGROUND: Elevated levels of corticotrophin-releasing hormone in the cortical-hippocampal-amygdala pathway increase fear and anxiety, which are components of defensive and violent behaviors. Prostaglandins E2 and F2alpha, which increase corticotrophin-releasing hormone RNA expression in this pathway, are reduced by dietary intakes of omega-3 fats. METHODS: Among 21 perpetrators of domestic violence, cerebrospinal fluid and plasma were assessed for corticotrophin-releasing hormone and fatty acid compositions, respectively. RESULTS: Lower plasma docosahexaenoic acid (wt% fatty acids) alone predicted greater cerebrospinal fluid corticotrophin-releasing hormone (pg/mL), in exponential (r = -.67, p < .006) and linear regressions (r = -0.68, p < .003 excluding four subjects with the highest docosahexaenate levels). CONCLUSIONS: In this small observational study, low plasma docosahexaenoic acid levels were correlated to higher cerebrospinal fluid corticotrophin-releasing hormone levels. Placebo controlled trials can determine if dietary omega-3 fatty acids can reduce excessive corticotrophin-releasing hormone levels in psychiatric illnesses.

Corticotropin-releasing factor in posttraumatic stress disorder (PTSD) with secondary psychotic symptoms, nonpsychotic PTSD, and healthy control subjects.

BACKGROUND: Recent studies have reported a high comorbidity between posttraumatic stress disorder (PTSD) and psychotic symptoms, and it has been hypothesized that PTSD with comorbid psychosis is a severe form of PTSD. Few studies have examined the neurobiology of PTSD with comorbid psychosis. If PTSD with secondary psychotic symptoms (PTSD-SP) is a severe form of PTSD, then it might be expected to show more extreme perturbations in the neuroendocrine patterns that characterize PTSD. METHODS: Patients with PTSD with secondary psychotic symptoms (PTSD-SP), PTSD without psychosis, and healthy comparison subjects were compared for differences in cerebrospinal fluid concentrations of corticotropin-releasing factor (CRF) and somatotropin-release-inhibiting hormone (SRIF). RESULTS: The PTSD-SP subjects had significantly higher mean levels of CRF than either the PTSD or control subjects (p <.01). The three groups showed similar SRIF levels. CONCLUSIONS: These data implicate abnormalities in the secretion of CRF with the production of secondary psychotic symptoms in PTSD. This finding supports the validity of PTSD-SP as a PTSD subtype and as a severe form of PTSD.

Elevated concentrations of CRF in the locus coeruleus of depressed subjects.

Research evidence that corticotropin-releasing factor (CRF) plays a role in the pathophysiology of major depressive disorder (MDD) has accumulated over the past 20 years. The elevation of lumbar cerebrospinal fluid (CSF) concentrations of CRF decreased responsiveness of pituitary CRF receptors to challenge with synthetic CRF, and increased levels of serum cortisol in MDD subjects support the hypothesis that CRF is chronically hypersecreted in at least the endocrine circuits of the hypothalamic-pituitary-adrenal (HPA) axis and may also involve other CRF brain circuits mediating emotional responses and/or arousal. One such circuit includes the excitatory CRF input to the locus coeruleus (LC), the major source of norepinephrine in the brain. Furthermore, there are now reports of decreased levels of CRF in lumbar CSF from MDD patients after symptom relief from chronic treatment with antidepressant drugs or electroconvulsive therapy. Whether this normalization reflects therapeutic effects on both endocrine- and limbic-associated CRF circuits has not yet been effectively addressed. In this brief report, we describe increased concentrations of CRF-like immunoreactivity in micropunches of post-mortem LC from subjects with MDD symptoms as established by retrospective psychiatric diagnosis compared to nondepressed subjects matched for age and sex.

CSF CRH in abstinent cocaine-dependent patients.

Alterations in stress responsivity may be important in the vulnerability to become cocaine dependent. Thus, an index of hypothalamic-pituitary-adrenal (HPA) axis function was examined in abstinent cocaine-dependent patients. Cerebrospinal fluid (CSF) concentrations of corticotropin releasing factor (CRH) were determined in 29 abstinent cocaine-dependent patients and 66 normal controls. The results showed that there was no significant difference between the abstinent cocaine-dependent patients and normal controls for CSF CRH. Also, CSF CRH concentrations were not related to cocaine-craving scores in a cue-elicited cocaine-craving procedure. Thus, these data suggest that after protracted abstinence from cocaine there is no marked dysregulation of CRH systems as measured by CSF CRH concentrations.

Regional Neuropeptide Pathology in Alzheimer's Disease: Corticotropin-Releasing Factor and Somatostatin.

BACKGROUND: the neuropeptides most consistently reported to be altered in Alzheimer's disease are corticotropin-releasing factor and somatostatin (somatotropin-release inhibiting factor), although this has been previously assessed in a limited number of brain regions. METHODS: in order to comprehensively characterize the involvement of these two anatomically distinct neuropeptide systems in Alzheimer's disease and to determine if they are equally involved in the associated pathology, we measured the concentration of corticotropin-releasing factor and somatostatin in post-mortem brain tissue. Radioimmunoassay of 24 cortical and 13 sub-cortical brain regions from 16 cases of neuropathologically confirmed AD and 9 non-Alzheimer's disease controls were performed and significant differences in group regional neuropeptide concentrations were sought using the Student Newman-Keuls test after ANOVA. RESULTS: comparison of group mean regional neuropeptide concentrations revealed several brain regions where both peptides were decreased in Alzheimer's disease and some regions where only one of the two peptides were decreased, while still other regions exhibited no changes in either peptide. These changes were principally found in frontal and temporal cortex, with few subcortical regions exhibiting pathologic changes in peptide concentration. Regional peptide content was correlated among peptides and with duration of dementia in several brain regions. CONCLUSIONS: these data support the hypothesis that the somatostatin- and corticotropin-releasing factor containing neurons are pathologically involved in AD and that the involved neurons are limited to specific areas of the brain.

Alterations in cerebrospinal fluid concentrations of somatostatin-like immunoreactivity in chronic pain patients.

Concentrations of somatostatin-like immunoreactivity in cerebrospinal fluid were significantly reduced in chronic pain patients compared to control patients without chronic pain. This difference was not influenced by demographic or clinical characteristics. Somatostatin has been shown to be a neurotransmitter in animal nociception; pharmacologic doses of this substance have moderated human pain. Our findings provide evidence that somatostatin may be involved in the pathogenesis of the chronic pain state.