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Exposure to juvenile stress exacerbates the behavioural consequences of exposure to stress in the adult rat

To examine the effects of exposure to post-weaning pre-puberty (juvenile) stress on the emotional and cognitive abilities in response to exposure to stress in adulthood, we first exposed rats to a platform stress at the age of 28 d. Two months later the rats were exposed to acute swim stress. Rats exposed to both stressors showed a higher level of anxiety (as measured both in open-field and startle response tests) than controls or rats exposed to either the juvenile or the adulthood stressor. In the Morris water-maze, rats that were exposed to both juvenile and adulthood stress performed better than the other groups. In a second experiment we verified that the effect of the juvenile stress was indeed age-dependent. One group was exposed at the age of 26-28 d and again at the age of 60 d (juvenile + adulthood stress); the other group was exposed to the first stressor at the age of 60-62 d and to the second at the age of 90 d [adulthood (60) + adulthood (90) stress]. Juvenile + adulthood stress had a significantly greater effect than exposure to stress twice in adulthood, on anxiety level and on the performance in the water-maze. Finally, in a third experiment we found that the juvenile+adulthood stress group swam faster and tended to explore the central area more than the other groups--a finding that could explain their better performance on the first trial of the spatial task. These results indicate that an exposure to a relatively brief juvenile stressful experience has profound and long-lasting effects on the ability to cope with stress in adulthood.

Reversible modulations of neuronal plasticity by VEGF

Neurons, astrocytes, and blood vessels are organized in functional “neurovascular units” in which the vasculature can impact neuronal activity and, in turn, dynamically adjust to its change. Here we explored different mechanisms by which VEGF, a pleiotropic factor known to possess multiple activities vis-à-vis blood vessels and neurons, may affect adult neurogenesis and cognition. Conditional transgenic systems were used to reversibly overexpress VEGF or block endogenous VEGF in the hippocampus of adult mice. Importantly, this was done in settings that allowed the uncoupling of VEGF-promoted angiogenesis, neurogenesis, and memory. VEGF overexpression was found to augment all three processes, whereas VEGF blockade impaired memory without reducing hippocampal perfusion or neurogenesis. Pertinent to the general debate regarding the relative contribution of adult neurogenesis to memory, we found that memory gain by VEGF overexpression and memory impairment by VEGF blockade were already evident at early time points at which newly added neurons could not yet have become functional. Surprisingly, VEGF induction markedly increased in vivo long-term potentiation (LTP) responses in the dentate gyrus, and VEGF blockade completely abrogated LTP. Switching off ectopic VEGF production resulted in a return to a normal memory and LTP, indicating that ongoing VEGF is required to maintain increased plasticity. In summary, the study not only uncovered a surprising role for VEGF in neuronal plasticity, but also suggests that improved memory by VEGF is primarily a result of increasing plasticity of mature neurons rather than the contribution of newly added hippocampal neurons.

Contrasting Roles of Corticosteroid Receptors in Hippocampal Plasticity

Elevated levels of corticosteroid hormones, presumably occupying both mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs), have been reported to impair synaptic plasticity in the hippocampus as well as the acquisition of hippocampus-dependent memories. In contrast, recent evidence suggests that activation of MRs enhance cognitive functions. To clarify the roles of different steroid receptors in hippocampal plasticity, young adult rats were injected with the GR antagonist RU38486 (mifepristone) or the MR antagonist Spironolactone before the exposure to an acute swim stress. Hippocampal responses to perforant path stimulation were then recorded in anesthetized rats. Stress combined with RU38486 produced a striking facilitation of LTP. Spironolactone enabled only short-term potentiation that reversed to long-term depression (LTD) in the stressed animals. Finally, the blockade of both MRs and GRs led to impairment of long-term potentiation. These findings indicate that MRs and GRs assume opposite roles in regulation of synaptic plasticity after acute exposure to stressors.

Morphological changes in hippocampal dentate gyrus synapses following spatial learning in rats are transient

The hippocampus is believed to play a crucial role in the formation of memory for spatial tasks. In the present study quantitative electron microscopy was used to investigate morphological changes in the hippocampal dentate gyrus of 3‐month‐old male rats at 3, 9 and 24 h after training to find a hidden platform in a Morris water maze. Average escape latency (time taken to reach the platform) in all trained groups decreased progressively with increased training but data from a probe trial (quadrant analysis test) at the end of training indicated that only animals in the 9‐ and 24‐h groups, not the 3‐h group, displayed significant retention of platform location. Unbiased stereological methods were used to estimate synapse and neuronal density at each time point after training. The majority of synapses had unperforated postsynaptic densities, were localized on small dendritic spines and were classed as axo‐spinous. In comparison to age‐matched untrained rats, significant but transient increases were observed in axo‐spinous synapse density and synapse‐to‐neuron ratio 9 h after the start of training, but not at earlier (3 h) or later (24 h) times. These changes at 9 h post‐training were accompanied by transient decreases in both mean synaptic height and area of postsynaptic density. No such changes were observed in an exercise‐matched control group of rats, indicating that the transient synaptic changes in the dentate gyrus are most likely to be specifically related to processes involved in memory formation for the spatial learning task.

The SSRIs drug Fluoxetine, but not the noradrenergic tricyclic drug Desipramine, improves memory performance during acute major depression

Accumulating evidence suggests that noradrenergic and serotonergic drugs are equally effective in ameliorating the depressive symptoms of major depression. Major depression is associated also with memory impairments, but the comparative effects of the antidepressant drugs on memory are not clear. We previously found that serotonergic neurotransmission is of particular importance for some aspects of episodic memory. We set out to test whether treatment with the selective serotonergic drug Fluoxetine (Prozac) would be advantageous in this respect over treatment with the selective noradrenergic tricyclic antidepressant drug Desipramine (Deprexan). Seventeen patients with major depressive episode, randomly assigned for treatment with either Fluoxetine (n = 8) or Desipramine (n = 9), were assessed for their clinical situation and for memory performance at the beginning of treatment, after 3 weeks, and after 6 weeks of pharmacological treatment. We found that although clinically both drugs were equally effective, the improvement of memory performance in the Fluoxetine-treated patients was significantly greater compared with that of the Desipramine-treated patients. The results support the role of serotonin in memory. More studies in larger samples of patients are required, but it may be that in cases where memory impairment is a major symptom, it would be beneficial to consider serotonergic antidepressant drugs for treatment. Furthermore, in cases where, for various reasons, the treatment of choice is noradrenergic, it may be worthwhile to consider a supplementary serotonergic drug to improve memory deficits.

Effects of early-life stress on behavior and neurosteroid levels in the rat hypothalamus and entorhinal cortex.

Recent evidence support the hypothesis that exposure to stress or trauma during early childhood may disturb the formation of functional brain pathways, in particular, of the limbic circuits. We examined the effects of exposure to early life trauma (juvenile stress) on emotional and cognitive aspects of behavior in adulthood as well as on dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) levels in relevant brain regions. Quantitative assessment of the effects of exposure to juvenile stress was made 1 month post-stress, and obtained by measuring: emotional (utilizing an open field and a startle response tests) and cognitive (Morris water-maze task) functions, as well as neurosteroids concentration (DHEA and its sulfate ester, DHEAS) in the hypothalamus and entorhinal cortex. We report here that an exposure to juvenile stress led to elevated levels of anxiety 1 month post-stress. Moreover, in a spatial learning task, the juvenile stress group performed poorer than the control group. Finally, an exposure to juvenile stress increased DHEAS but not DHEA concentrations both in the hypothalamus and the entorhinal cortex. These findings indicate that an exposure to juvenile stress has long-lasting effects on behavior and DHEAS levels in the hypothalamus and the entorhinal cortex. These effects may be of relevance to our understanding of early life stress-related disorders such as PTSD and major depression.

Astrocytes support hippocampal-dependent memory and long-term potentiation via interleukin-1 signaling.

Recent studies indicate that astrocytes play an integral role in neural and synaptic functioning. To examine the implications of these findings for neurobehavioral plasticity we investigated the involvement of astrocytes in memory and long-term potentiation (LTP), using a mouse model of impaired learning and synaptic plasticity caused by genetic deletion of the interleukin-1 receptor type I (IL-1RI). Neural precursor cells (NPCs), derived from either wild type (WT) or IL-1 receptor knockout (IL-1rKO) neonatal mice, were labeled with bromodeoxyuridine (BrdU) and transplanted into the hippocampus of either IL-1rKO or WT adult host mice. Transplanted NPCs survived and differentiated into astrocytes (expressing GFAP and S100β), but not to neurons or oligodendrocytes. The NPCs-derived astrocytes from WT but not IL-1rKO mice displayed co-localization of GFAP with the IL-1RI. Four to twelve weeks post-transplantation, memory functioning was examined in the fear-conditioning and the water maze paradigms and LTP of perforant path-dentate gyrus synapses was assessed in anesthetized mice. As expected, IL-1rKO mice transplanted with IL-1rKO cells or sham operated displayed severe memory disturbances in both paradigms as well as a marked impairment in LTP. In contrast, IL-1rKO mice transplanted with WT NPCs displayed a complete rescue of the impaired memory functioning as well as partial restoration of LTP. These findings indicate that astrocytes play a critical role in memory functioning and LTP, and specifically implicate astrocytic IL-1 signaling in these processes. The results suggest novel conceptualization and therapeutic targets for neuropsychiatric disorders characterized by impaired astrocytic functioning concomitantly with disturbed memory and synaptic plasticity.

Environmental Enrichment Restores Memory Functioning in Mice with Impaired IL-1 Signaling via Reinstatement of Long-Term Potentiation and Spine Size Enlargement

Environmental enrichment (EE) was found to facilitate memory functioning and neural plasticity in normal and neurologically impaired animals. However, the ability of this manipulation to rescue memory and its biological substrate in animals with specific genetically based deficits in these functions has not been extensively studied. In the present study, we investigated the effects of EE in two mouse models of impaired memory functioning and plasticity. Previous research demonstrated that mice with a deletion of the receptor for the cytokine interleukin-1 (IL-1rKO), and mice with CNS-specific transgenic over-expression of the IL-1 receptor antagonist (IL-1raTG) display impaired hippocampal memory and long-term potentiation (LTP). We report here a corrective effect of EE on spatial and contextual memory in IL-1rKO and IL-1raTG mice and reveal two mechanisms for this beneficial effect: Concomitantly with their disturbed memory functioning, LTP in IL-1rKO mice that were raised in a regular environment is impaired, and their dendritic spine size is reduced. Both of these impairments were corrected by environmental enrichment. No deficiencies in neurogenesis or hippocampal BDNF and vascular endothelial growth factor secretion were found in IL-1rKO mice that were raised in a regular environment, and both of these variables were increased to a similar degree in enriched IL-1rKO and wild-type mice. These findings suggest that exposure to an enriched environment may be beneficial for individuals with impaired learning and memory related to genetic impairments of IL-1 signaling (and possibly other genetic causes), by reversing impairments in dentate gyrus LTP and spine size and by promoting neurogenesis and trophic factors secretion.

Acute and Repeated Swim Stress Effects on Peripheral Benzodiazepine Receptors in the Rat Hippocampus, Adrenal, and Kidney ☆ ☆☆

Peripheral benzodiazepine receptor (PBR) density has been found to be sensitive to stress. We set out to compare the influences of acute and repeated swim stress on behavior and PBR density. Following acute and repeated swim stress, rats were tested in an elevated plus-maze and an open-field test for anxiety levels, and tissues were collected from the adrenal gland, kidney, and hippocampus for measurements of PBR density. The acute rather than the repeated stress led to robust alterations in PBR density. The largest reduction in hippocampal and adrenal gland PBR density was found one hour after acute stress. In the hippocampus, acute stress caused a biphasic change in PBR density: a robust reduction in PBR density one hour after the acute stress and a distinct elevation in PBR density at 24 hours, while 72 hours after stress the elevation in PBR density appeared to be reduced.

Role of Mental Retardation-Associated Dystrophin-Gene Product Dp71 in Excitatory Synapse Organization, Synaptic Plasticity and Behavioral Functions

Background Duchenne muscular dystrophy (DMD) is caused by deficient expression of the cytoskeletal protein, dystrophin. One third of DMD patients also have mental retardation (MR), likely due to mutations preventing expression of dystrophin and other brain products of the DMD gene expressed from distinct internal promoters. Loss of Dp71, the major DMD-gene product in brain, is thought to contribute to the severity of MR; however, the specific function of Dp71 is poorly understood. Methodology/Principal Findings Complementary approaches were used to explore the role of Dp71 in neuronal function and identify mechanisms by which Dp71 loss may impair neuronal and cognitive functions. Besides the normal expression of Dp71 in a subpopulation of astrocytes, we found that a pool of Dp71 colocalizes with synaptic proteins in cultured neurons and is expressed in synaptic subcellular fractions in adult brains. We report that Dp71-associated protein complexes interact with specialized modular scaffolds of proteins that cluster glutamate receptors and organize signaling in postsynaptic densities. We then undertook the first functional examination of the brain and cognitive alterations in the Dp71-null mice. We found that these mice display abnormal synapse organization and maturation in vitro, altered synapse density in the adult brain, enhanced glutamatergic transmission and reduced synaptic plasticity in CA1 hippocampus. Dp71-null mice show selective behavioral disturbances characterized by reduced exploratory and novelty-seeking behavior, mild retention deficits in inhibitory avoidance, and impairments in spatial learning and memory. Conclusions/Significance Results suggest that Dp71 expression in neurons play a regulatory role in glutamatergic synapse organization and function, which provides a new mechanism by which inactivation of Dp71 in association with that of other DMD-gene products may lead to increased severity of MR.