Venlafaxine reverses decreased proliferation in the subventricular zone in a rat model of early life stress.

It is believed that glucocorticoids control the proliferation of neural progenitor cells, and this process is highly involved in mood disorders and cognitive processes. Using the maternal separation model of chronic neonatal stress, it has been found that stress induced depressive-like behavior, cognitive deficits and a decrease in proliferation in the subventricular zone (SVZ). Venlafaxine reversed all deleterious effects of chronic stress by modulating HPA activity. These outcomes suggest modulation of stress-mediated glucocorticoid secretion as a target for the treatment of mood disorders and neurodegenerative processes.

Stress contributes to the development of central insulin resistance during aging: implications for Alzheimer's disease.

It is becoming evident that chronic exposure to stress not only might result in insulin resistance or cognitive deficits, but may also be considered a risk factor for pathologies such as depression or Alzheimer's disease (AD). There is great interest in determining the molecular mechanisms underlying interactions between stress, aging, memory and Alzheimer's disease (AD). We have used the chronic mild stress (CMS) model to study the effects of chronic stress on the aging process and the development of central insulin resistance and AD pathology. CMS aged mice showed cognitive impairments in the novel object recognition test. In addition, CMS aged mice displayed both peripheral insulin resistance, as shown by HOMA index, and decreased hippocampal levels of pIRS and downstream intracellular signaling (pAKT, pGSK and pERK1/2). Interestingly, there was a significant increase in both C99:C83 ratio and BACE1 levels in the hippocampus of CMS aged mice. Increased expression of the AD marker pTau was also found in stressed aged mice. Increased expression of the stress-activated protein kinase JNK was found in CMS aged mice, accompanied by significant decreases in glucocorticoid receptor (GR) expression and increases in mineralocorticoid receptor (MR) expression. It is suggested that the interaction of stress with aging should be considered when studying determinants of the onset and progression of AD.

Effects of early maternal separation on biobehavioral and neuropathological markers of Alzheimer's disease in adult male rats.

Stress has been described as a risk factor for the development of Alzheimer´s disease (AD). In the present work we aim to study the validity of an experimental model of neonatal chronic stress in order to recapitulate the main hallmarks of AD. Male Wistar rats that were separated daily from the dam during the first 3 weeks of life (maternal separation, MS) showed in adulthood cognitive deficits novel object recognition test. In the hippocampus of MS rats, increases in both Aß40 and Aß42 levels, the principal constituent of amyloid plaques observed in AD, were accompanied by increased expression of the cleaving enzyme BACE1. Hyperphosphorylation of Tau associated to increased activation of the tau kinase JNK1 was also found. Decreased cell number in the hippocampus was observed in stressed rats, as a consequence of both decreased cell proliferation and increased apoptotic death. Decreases in BDNF and in the synaptic markers synaptophysin and PSD-95 were also found in MS rats. All these effects could be related to an HPA axis hyperactivity, as reflected in significant increases in corticosterone levels and decreases in glucocorticoid receptor expression. Further, SHSY5Y neuroblastoma cells treated with corticosterone showed increased BACE1, pTau and pJNK1 expression. In addition, venlafaxine, an antidepressant able to modulate HPA axis activity, reversed all the above cited deleterious effects of chronic stress, both in vivo and in vitro. It is proposed that the MS model can be considered as an appropriate experimental model for the study of sporadic AD.

Maternal deprivation effects on brain plasticity and recognition memory in adolescent male and female rats.

Data from both human and animal studies suggest that exposure to stressful life events at neonatal stages may increase the risk of psychopathology at adulthood. In particular, early maternal deprivation, 24 h at postnatal day (pnd) 9, has been associated with persistent neurobehavioural changes similar to those present in developmental psychopathologies such as depression and schizophrenic-related disorders. Most neuropsychiatric disorders first appear during adolescence, however, the effects of MD on adolescent animals' brain and behaviour have been scarcely explored. In the present study, we aimed to investigate the emotional and cognitive consequences of MD in adolescent male and female rats, as well as possible underlying neurobiological mechanisms within frontal cortex and hippocampus. Animals were exposed to a battery of behavioural tasks, from pnd 35 to 42, to evaluate cognitive [spontaneous alternation task (SAT) and novel object test (NOT)] and anxiety-related responses [elevated plus maze (EPM)] during adolescence. Changes in neuronal and glial cells, alterations in synaptic plasticity as well as modifications in cannabinoid receptor expression were investigated in a parallel group of control and adolescent (pnd 40) male and female animals. Notably, MD induced a significant impairment in recognition memory exclusively among females. A generalized decrease in NeuN expression was found in MD animals, together with an increase in hippocampal glial fibrillar acidic protein (GFAP) expression exclusively among MD adolescent males. In addition, MD induced in the frontal cortex and hippocampus of male and female adolescent rats a significant reduction in brain derived neurotrophic factor (BDNF) and postsynaptic density (PSD95) levels, together with a decrease in synaptophysin in frontal cortex and neural cell adhesion molecule (NCAM) in hippocampus. MD induced, in animals of both sexes, a significant reduction in CB1R expression, but an increase in CB2R that was statistically significant only for the frontal cortex. Taken together, these results indicate that adolescent females are more vulnerable than males to the cognitive deficits derived from MD despite the changes in neural cells, cannabinoid receptors, as well as the reduction in neural plasticity seem to be similar in both sexes. Further investigation is needed to understand the neurobiological mechanisms underlying the sexual dimorphisms associated to the MD effects, and thus, for a better understanding of the specific sex-dependent vulnerabilities to early life stress. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'.

Cholinergic denervation exacerbates amyloid pathology and induces hippocampal atrophy in Tg2576 mice.

The main pathological hallmarks of Alzheimer's disease (AD) consist of amyloid plaques and neurofibrillary tangles. Hippocampal cell loss, atrophy and cholinergic dysfunction are also features of AD. The present work is aimed at studying the interactions between cholinergic denervation, APP processing and hippocampal integrity. The cholinergic immunotoxin mu p-75-saporin was injected into the 3rd ventricle of 6- to 8-month-old Tg2576 mice to induce a cholinergic denervation. Four weeks after cholinergic immunolesion, a significant 14-fold increase of soluble Aß1-42 was observed. Cholinergically lesioned Tg2576 mice showed hippocampal atrophy together with degenerating FluoroJade-B-stained neurons and reduction of synaptophysin expression in CA1-3 pyramidal layers. We also found that cholinergic denervation led to reduced levels of ADAM17 in hippocampus of Tg2576 mice. Inhibition of ADAM17 with TAPI-2 (5 µM) decreased viability of hippocampal primary neurons from Tg2576 brains and decreased phosphorylation of downstream effectors of trophic signalling (ERK and Akt). The cholinergic agonist carbachol (100 µM) rescued these effects, suggesting that cholinergic deficits might render hippocampus more vulnerable to neurotoxicity upon certain toxic environments. The present work proposes a novel model of AD that worsens the patent amyloid pathology of Tg2576 mice together with hippocampal synaptic pathology and neurodegeneration. Drugs aimed at favoring cholinergic transmission should still be considered as potential treatments of AD.

Novel benzo[b]thiophene derivatives as new potential antidepressants with rapid onset of action.

We report benzo[b]thiophene derivatives synthesized according to a dual strategy. 8j, 9c, and 9e with affinity values toward 5-HT(7)R and 5-HTT were selected to probe their antidepressant activity in vivo using the forced swimming text (FST). The results showed significant antidepressant activity after chronic treatment. 9c was effective in reducing the immobility time in FST even after acute treatment. These findings identify these compounds as a new class of antidepressants with a rapid onset of action.

HPA axis dysregulation associated to apolipoprotein E4 genotype in Alzheimer's disease.

The present work investigated the involvement of cortisol and its receptors, glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), in Alzheimer's disease (AD). Cortisol was measured in cerebrospinal fluid (CSF) samples from controls, mild cognitive impairment (MCI), progressive MCI evolving to AD, and AD. CSF cortisol levels do not seem to have a prognostic value, as increases in cortisol levels were found only in AD patients. GR expression was decreased while MR expression was increased in the frontal cortex of AD. When considering degeneration (ratio to synaptophysin and the post-synaptic marker PSD95), GR expression was similar between controls and AD, suggesting that GR loss was due to synaptic degeneration in AD. Increases in cortisol levels and MR expression were associated to an apolipoprotein E4 genotype. Cognitive status was negatively associated to CSF cortisol. In apolipoprotein E4 carriers, MR but not GR expression, negatively correlated to Mini-Mental Status Examination score and positively correlated to frontal cortex amyloid-ß levels. It is concluded that there is a dysregulation of the hypothalamus-pituitary-adrenal axis in AD that seems to be consequence rather than cause of AD.

Interactions between age, stress and insulin on cognition: implications for Alzheimer's disease.

There is much interest in understanding the mechanisms responsible for interactions among stress, aging, memory and Alzheimer's disease. Glucocorticoid secretion associated with early life stress may contribute to the variability of the aging process and to the development of neuro- and psychopathologies. Maternal separation (MS), a model of early life stress in which rats experience 3 h of daily separation from the dam during the first 3 weeks of life, was used to study the interactions between stress and aging. Young (3 months) MS rats showed an altered hypothalamic-pituitary-adrenal (HPA) axis reactivity, depressive-like behavior in the Porsolt swimming test and cognitive impairments in the Morris water maze and new object recognition test that persisted in aged (18 months) rats. Levels of insulin receptor, phosphorylated insulin receptor and markers of downstream signaling pathways (pAkt, pGSK3 beta, pTau, and pERK1 levels) were significantly decreased in aged rats. There was a significant decrease in pERK2 and in the plasticity marker ARC in MS aged rats compared with single MS or aged rats. It is interesting to note that there was a significant increase in the C99 : C83 ratio, A beta levels, and BACE1 levels the hippocampus of MS aged rats, suggesting that in aged rats subjected to early life stress, there was an increase in the amyloidogenic processing of amyloid precursor protein (APP). These results are integrated in a tentative mechanism through which aging interplay with stress to influence cognition as the basis of Alzheimer disease (AD). The present results may provide the proof-of-concept for the use of glucocorticoid-/insulin-related drugs in the treatment of AD.

Altered NCAM expression associated with the cholinergic system in Alzheimer's disease.

Neurotransmitter system dysfunction and synapse loss have been recognized as hallmarks of Alzheimer's disease (AD). Our hypothesis is that specific neurochemical populations of neurons might be more vulnerable to degeneration in AD due to particular deficits in synaptic plasticity. We have studied, in postmortem brain tissue, the relationship between levels of synaptic markers (NCAM and BDNF), neurochemical measurements (cholinacetyltransferase activity, serotonin, dopamine, GABA, and glutamate levels), and clinical data (cognitive status measured as MMSE score). NCAM levels in frontal and temporal cortex from AD patients were significantly lower than control patients. Interestingly, these reductions in NCAM levels were associated to an ApoE4 genotype. Levels of BDNF were also significantly reduced in both frontal and temporal regions in AD patients. The ratio between plasticity markers and neurochemical measurements was used to study which of the neurochemical populations was particularly associated to plasticity changes. In both the frontal and temporal cortex, there was a significant reduction in the ChAT/NCAM ratio in AD samples compared to controls. None of the ratios to BDNF were different between control and AD samples. Furthermore, Pearson's product moment showed a significant positive correlation between MMSE score and the ChAT/NCAM ratio in frontal cortex (n=19; r=0.526*; p=0.037) as well as in temporal cortex (n=19; r=0.601*; p=0.018) in AD patients. Altogether, these data suggest a potential involvement of NCAM expressing neurons in the cognitive deficits in AD.

Signalling pathways associated with 5-HT6 receptors: relevance for cognitive effects.

A growing body of evidence supports the use of serotonin 5-HT6 receptor antagonists as a promising mechanism for treating cognitive dysfunction. We evaluated 5-HT6 receptor expression and associated biochemical mechanisms in the hippocampus of rats that had been trained in the Morris water maze (MWM), a spatial learning task. Training in the MWM induces a down-regulation of 5-HT6 receptor protein and mRNA receptor expression. The learning procedure or the administration of the selective 5-HT6 receptor antagonist SB-271046 induced an increase in pCREB1 levels while CREB2 levels were significantly reduced. However, although SB-271046 was able to improve retention in the MWM, no further changes in pCREB1 or CREB2 levels were found to be associated with the presence of the 5-HT6 receptor antagonist during the learning procedure. The MWM procedure significantly increased pERK1/2 levels and interestingly, further increases were seen when treating with SB-271046 during the MWM. These results suggest that, in the hippocampus, biochemical pathways associated with pERK1/2 expression, and not with the CREB family of transcription factors, seem to be related to the cognitive-enhancing properties of 5-HT6 receptor antagonists.

Neonatal stress affects vulnerability of cholinergic neurons and cognition in the rat: involvement of the HPA axis.

Adverse experiences early in life may sensitize specific neurocircuits to subsequent stressors. We have evaluated in maternal separation (MS) rats, an animal paradigm of early-life stress, the effects of a selective cholinergic lesion on cognitive function as well as susceptibility of cholinergic neurons to the lesion. MS rats subjected to a cholinergic lesion by administration of the immunotoxin 192 IgG-saporin, showed significant decreases in both choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activity compared to control lesioned rats. Morris water maze results revealed a significant impairment in learning and memory function in MS adult rats and further cognitive deficits after the lesion. The lesion of cholinergic neurons induced a significant decrease in glucocorticoid receptor density in MS rats, accompanied by increases in CRF mRNA expression. Decreases in NGF and increases in NGF-p75NTR expression have also been found in MS rats. Our results suggest that vulnerability of basal forebrain cholinergic nerve cells might be affected by the HPA axis. The present data are discussed not only in terms of conditions that occur during ageing or Alzheimer disease, but also regarding a purported involvement of the cholinergic system in the regulation of HPA axis activity.

Effects of neonatal stress on markers of synaptic plasticity in the hippocampus: implications for spatial memory.

Early stressful adverse situations may increase the vulnerability to cognitive deficits and psychiatric disorders, such as depression. Maternal separation (MS) has been used as an animal model to study changes in neurochemistry and behavior associated with exposure to early-life stress. This study investigated the effects of neonatal stress (MS) on the expression of synaptic plasticity markers in the hippocampus and a purported relationship to cognitive processes. Spatial learning (Morris water maze) significantly increased the expression of total levels of the neural cell adhesion molecule (NCAM), as well as its three major isoforms (NCAM-120, -140, and -180) both in the control and MS groups. Interestingly, these increases in NCAM expression after learning were lower in MS animals when compared with control rats. MS induced a significant decrease in total levels of NCAM, and specifically, in the NCAM-140 isoform expression. In the hippocampus of MS rats there was a significant decrease in brain-derived neurotrophic factor and synaptophysin mRNA densities. Cell proliferation, measured as BrdU-positive cells, was also decreased in the dentate gyrus of MS rats. Altogether these results suggest that MS can alter normal brain development, providing a potential mechanism by which early environmental stressors may influence vulnerability to show cognitive impairments later in life.

Increase of locomotor activity underlying the behavioral disinhibition in tg2576 mice.

The transgenic Tg2576 mouse is a widely used animal model that develops some of the cognitive and neuropathological deteriorations observed in patients suffering Alzheimer's disease. The authors investigated 9-month-old Tg2576 mice with respect to behavioral and endocrinological (hypothalamic- pituitary-adrenal [HPA] axis activity) parameters. The locomotor activity test revealed that Tg2576 mice moved almost twice as much as controls. Tg2576 mice spent significantly more time visiting the open arms and performed more entries into these open arms than did controls. However, the amount of time that Tg2576 mice remained in each entry to the open arm was similar to that of controls, and the number of arm entries correlated positively to locomotor activity. In the forced swimming test, Tg2576 mice showed a significant decrease in immobility time, which correlated negatively to locomotor activity. Parameters of the HPA axis, such as plasma level of corticosterone, adrenal gland weight, and noradrenaline or adrenaline release, did not differ between controls and Tg2576 mice. These data suggest that the disinhibitory behavior of Tg2576 mice seems to be related to increased locomotor activity but not to any disturbance of the HPA axis.

Cognitive impairment associated to HPA axis hyperactivity after maternal separation in rats.

Exposure to early stressful adverse life events may increase vulnerability to psychopathology in adult life. There are important memory disturbances in stress-related psychiatric disorders. Therefore, there is much interest in understanding the mechanisms responsible for interactions between stress and cognition. Male Wistar rats that experienced 3-h daily separations from the dam during the first 3 weeks of life (maternal separation, MS) showed in adulthood a depressive-like behaviour in the forced swimming test, increased hypothalamic-pituitary-adrenal (HPA) axis responsiveness to stressors and elevated CRF mRNA in the paraventricular nucleus of the hypothalamus (PVN). In the hippocampus of MS rats, there was a lower glucocorticoid receptor density. MS produced significant learning impairments both in the Morris water maze and in the novel object recognition test (NORT). The glucocorticoid receptor antagonist mifepristone and the beta-adrenoceptor antagonist propranolol were able to completely reverse the increased immobility time in the forced swimming test and the memory deficits in the NORT observed in MS rats. Our data support the hypothesis that elevated secretion of glucocorticoids may be associated to behavioural and cognitive deficits in MS rats. The stress hyperresponsiveness observed in MS rats could be attributed, at least in part, to an impaired feedback sensitivity mediated by hippocampal glucocorticoid receptors. It can also be suggested the possible involvement of the noradrenergic system in cognitive impairments mediated by glucocorticoids in the MS model.