Aging Alters Daily and Regional Calretinin Neuronal Expression in the Rat Non-image Forming Visual Thalamus.

Aging affects the overall physiology, including the image-forming and non-image forming visual systems. Among the components of the latter, the thalamic retinorecipient inter-geniculate leaflet (IGL) and ventral lateral geniculate (vLGN) nucleus conveys light information to subcortical regions, adjusting visuomotor, and circadian functions. It is noteworthy that several visual related cells, such as neuronal subpopulations in the IGL and vLGN are neurochemically characterized by the presence of calcium binding proteins. Calretinin (CR), a representative of such proteins, denotes region-specificity in a temporal manner by variable day-night expression. In parallel, age-related brain dysfunction and neurodegeneration are associated with abnormal intracellular concentrations of calcium. Here, we investigated whether daily changes in the number of CR neurons are a feature of the aged IGL and vLGN in rats. To this end, we perfused rats, ranging from 3 to 24 months of age, within distinct phases of the day, namely zeitgeber times (ZTs). Then, we evaluated CR immunolabeling through design-based stereological cell estimation. We observed distinct daily rhythms of CR expression in the IGL and in both the retinorecipient (vLGNe) and non-retinorecipient (vLGNi) portions of the vLGN. In the ZT 6, the middle of the light phase, the CR cells are reduced with aging in the IGL and vLGNe. In the ZT 12, the transition between light to dark, an age-related CR loss was found in all nuclei. While CR expression predominates in specific spatial domains of vLGN, age-related changes appear not to be restricted at particular portions. No alterations were found in the dark/light transition or in the middle of the dark phase, ZTs 0, and 18, respectively. These results are relevant in the understanding of how aging shifts the phenotype of visual related cells at topographically organized channels of visuomotor and circadian processing.

Prenatal restraint stress impairs recognition memory in adult male and female offspring.

OBJECTIVE: Accumulating evidence from preclinical and clinical studies indicates that prenatal exposure to stress impairs the development of the offspring brain and facilitates the emergence of mental illness. This study aims to describe the impact of prenatal restraint stress on cognition and exploration to an unfamiliar environment at adulthood in an outbred strain of mice. METHODS: Late pregnant mice were exposed to restraint stress and adult offspring (60 days of age) behaviours were assessed in the object recognition task and open field test. FINDINGS: Prenatal stress (PNS) impaired new object recognition in male and female mice. Importantly, the learning deficits in female PNS mice were linked to their estrous cycle. Actually, PNS females in metestrus/diestrus but not in proestrus/estrus phases displayed recognition deficits compared to controls. Concerning locomotion in an unfamiliar environment, male but not female PNS mice displayed significant increase, but showed no differences in the distance travelled within the centre zone of the arena. CONCLUSION: Present findings support the view that maternal restraint-stress during late pregnancy impairs recognition memory in both male and female offspring, and in females, this cognitive deficit is dependent on the estrous cycle phase. Ultimately, these data reinforce that PNS is an aetiological component of psychiatric disorders associated with memory deficits.

Venlafaxine and nortriptyline reverse acute dexamethasone-induced depressive-like behaviors in male and female mice.

Major depression can be triggered by stressful events that promote deregulation of the hypothalamic-pituitary-adrenal axis response and, in some circumstances, persistent elevation of circulating glucocorticoid levels. Animal models are widely used to investigate the mechanisms responsible for the etiology and treatment of major depression. However, to mimic the dysfunction of the hypothalamic-pituitary-adrenal axis in rodents, animals should be exposed to sustained physical and psychological stressful situations. These animal models of depression are labor intensive and impact individual animals differently. Aiming to add evidence for a new acute neuroendocrine model of depression, male and female mice were treated with a single administration of dexamethasone, and behavioral effects were evaluated in the presence and absence of the antidepressants nortriptyline and venlafaxine. Male and female Swiss mice were treated with dexamethasone (0.07 mg/kg, subcutaneously) and the mouse behavior was assessed in the tail suspension and open field tests at 4 h, 24 h, and 7 days after administration. Dexamethasone induced depressogenic-like states in both sexes at 4 and 24 h after injection. Additionally, acute dexamethasone increased latency to body fur licking, thus corroborating the depressive-like behavior. The treatment with nortriptyline and venlafaxine (both at 30 mg/kg, intraperitoneally) blocked dexamethasone-induced increase in the immobility time and the latency to self-care. In conclusion, the present findings suggest that a single administration of dexamethasone induces depressive-like states in male and female mice, and these behavioral alterations are counteracted by conventional antidepressants. Ultimately, these data provide new evidence for an acute neuroendocrine model of depression. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Subtle Alterations in Spatial Memory Induced by Amyloid Peptides Infusion in Rats.

The cause of Alzheimer's disease (AD) remains uncertain. The accumulation of amyloid peptides (Aß) is the main pathophysiological hallmark of the disease. Spatial deficit is an important initial sign of AD, while other types of memory impairments that appear in later stages. The Barnes maze allows the detection of subtle alterations in spatial search by the analysis of use of different strategies. Previous findings showed a general performance deficit in this task following long-term (35 days) infusion of Aß, which corresponds to the moderate or severe impairments of the disease. In the present study, we evaluated the effects of a low-dose 15-day long treatment with Aß peptides on spatial and non-spatial strategies of rats tested in the Barnes maze. Aß peptides (0.5 µL/site/day; 30 pmoL solution of Aß1-40:Aß1-42 10:1) or saline were bilaterally infused into the CA1 (on the first treatment day) and intraventricularly (on the following 15 days) in 6-month-old Wistar male rats. Aß infusion induced a deficit in the performance (increased latency and distance traveled to reach the target compared to saline group). In addition, a significant association between treatment and search strategy in the retrieval trial was found: Aß group preferred the non-spatial search strategy, while saline group preferred the spatial search. In conclusion, the protocol of Aß infusion used here induced a subtle cognitive deficit that was specific to spatial aspects. Indeed, animals under Aß treatment still showed retrieval, but using non-spatial strategies. We suggest that this approach is potentially useful to the study of the initial memory deficits in early AD.

Region-specific glial hyperplasia and neuronal stability of rat lateral geniculate nucleus during aging.

The normal aging process is accompanied by functional declines in image-forming and non-image forming visual systems. Among the components of these systems, the thalamic lateral geniculate nucleus (LGN) offers a good model for aging studies since its three anatomical subdivisions, namely dorsal lateral geniculate nucleus (dLGN), intergeniculate leaflet (IGL) and ventral lateral geniculate nucleus (vLGN), receives light information from retina and projects to different brain areas involved in visual-related functions. Nevertheless, there is very little data available about quantitative morphological aspects in LGN across lifespan. In this study, we used design-based stereology to estimate the number of neurons, glial cells, the glia/neuron ratio and the volume of the LGN of Wistar rats from 3, 13 or 23months of age. We examined each LGN subdivision processed by immunohistochemistry for NeuN and Nissl counterstain. We observed no significant age-related neuronal loss in any nuclei and a 21% and 33% significant increase in dLGN and IGL glial cells of 23month-old rats. We also observed the glia/neuron relation increases in dLGN of 13month-old rats and in dLGN, IGL and vLGN internal portion of 23month-old ones. Moreover, we report an age-related increase in IGL volume. These results show region-specific glial hyperplasia during aging within LGN nuclei, perhaps due to compensatory responses to inflammation. In addition, we observed the glia/neuron ratio as a more sensitive parameter to quantify age-related alterations. Hence, we provide an updated and expanded quantitative characterization of these visual-related thalamic nuclei and its variability across lifespan.

State-dependent effect of dopamine D1/D5 receptors inactivation on memory destabilization and reconsolidation.

Object recognition memories (ORM) can incorporate new information upon reactivation. This update initially involves destabilization of the original memory, which is followed by restabilization of the upgraded engram through a reconsolidation process that requires gene expression and protein synthesis in the hippocampus. We found that when given in dorsal CA1 either immediately after training or 15 min before ORM reactivation in the presence of a novel object, the dopamine D1/D5 receptor antagonist SCH23390 did not affect ORM consolidation, expression or retention but impeded the amnesia caused by the post-retrieval administration of the mRNA synthesis inhibitor α-amanitin or the protein synthesis blocker anisomycin. This anti-amnesic effect was not observed when SCH23390 was given immediately after training and again 15 min before memory reactivation. Our results demonstrate that hippocampal D1/D5 receptors are not needed for formation, retrieval or post-retrieval restabilization of the ORM trace but are essential for its destabilization when reactivation occurs together with the incorporation of new information into the original memory. Importantly, they also suggest that reenactment of the animal's post-learning neurochemical milieu at the moment of memory reactivation can be a boundary condition for reconsolidation.

Consolidation of object recognition memory requires HRI kinase-dependent phosphorylation of eIF2α in the hippocampus.

Local control of protein synthesis at synapses is crucial for synaptic plasticity and memory formation. However, little is known about the signals coupling neurotransmitter release with the translational machinery during these processes. Here, we studied the involvement of heme-regulated inhibitor (HRI) kinase, a kinase activated by nitric oxide that phosphorylates eukaryotic initiation factor 2α (eIF2α), in object recognition (OR) memory consolidation. Phosphorylated eIF2α mediates two opposing effects upon translation: translational arrest of most mRNAs and translational activation of selected mRNAs bearing specific features in their 5'untranslated regions (5'UTRs). We found that HRI kinase activation in the CA1 region of the dorsal hippocampus is necessary for retention of OR memory in rats. Accordingly, learning induced a transient increase in the phosphorylation state of eIF2α in dorsal CA1 which was abolished by the HRI kinase inhibitor N-(2,6-dimethylbenzyl)-6,7-dimethoxy-2H-[1]benzofuro[3,2-c]pyrazol-3-amine hydrochloride (AMI). The increase in p-eIF2α was associated with increased expression of BACE1 and activating transcription factor 4, two proteins containing eIF2α-responsive 5'UTRs in their mRNAs that play a key role in synaptic plasticity. Our data suggests that learning promotes the transient phosphorylation of eIF2α to allow for translation of specific 5'UTR-mRNAs through a process requiring HRI kinase activation.

Nicotine modulates the long-lasting storage of fear memory.

Late post-training activation of the ventral tegmental area (VTA)-hippocampus dopaminergic loop controls the entry of information into long-term memory (LTM). Nicotinic acetylcholine receptors (nAChR) modulate VTA function, but their involvement in LTM storage is unknown. Using pharmacological and behavioral tools, we found that α7-nAChR-mediated cholinergic interactions between the pedunculopontine tegmental nucleus and the medial prefrontal cortex modulate the duration of fear-motivated memories, maybe by regulating the activation state of VTA-hippocampus dopamine connections.

Infusion of protein synthesis inhibitors in the entorhinal cortex blocks consolidation but not reconsolidation of object recognition memory.

Memory consolidation and reconsolidation require the induction of protein synthesis in some areas of the brain. Here, we show that infusion of the protein synthesis inhibitors anisomycin, emetine and cycloheximide in the entorhinal cortex immediately but not 180 min or 360 min after training in an object recognition learning task hinders long-term memory retention without affecting short-term memory or behavioral performance. Inhibition of protein synthesis in the entorhinal cortex after memory reactivation involving either a combination of familiar and novel objects or two familiar objects does not affect retention. Our data suggest that protein synthesis in the entorhinal cortex is necessary early after training for consolidation of object recognition memory. However, inhibition of protein synthesis in this cortical region after memory retrieval does not seem to affect the stability of the recognition trace.

Age-dependent and age-independent human memory persistence is enhanced by delayed posttraining methylphenidate administration.

Healthy human volunteers 16-82 years of age with at least 10 years of schooling were exposed to two different memory tasks. The first task involved incidental memory. The subjects were asked, as casually as possible: "Did you watch any movie on TV 2 days ago? And 7 days ago? If so, do you remember the title of the movie(s) and the name of the first two actors (actresses)?" Retention scores (maximum = 3: title, actor 1, and actor 2) were equally high (overall mean = 2.6, n = 61) in all age groups (16-20, 21-30, 31-40, 41-60, and 61-82 years) for the day 2 scores. Scores for the movie seen 7 days before decreased significantly and progressively in the three older groups in relation to age, which indicates reduced persistence of this type of memory beginning at the age of 41-50 years and becoming more extensive over the years. The other task was a formal memory procedure. Subjects were asked to study a brief text with factual information on the 1954 World Soccer Cup for 10 min. They were then exposed to 10 questions on the text 2 days and, again, 7 days later. Retention scores declined between the two tests, but in this task, the decline of persistence occurred to a similar extent in all age groups, and thus was not dependent on age. Methylphenidate (10 mg p.o.) given 12 hours after acquisition markedly enhanced persistence of the two memory types. This suggests an involvement of dopaminergic processes in persistence in the late posttraining period.

Parallel memory processing by the CA1 region of the dorsal hippocampus and the basolateral amygdala.

There is abundant literature on the role of the basolateral amygdala (BLA) and the CA1 region of the hippocampus in memory formation of inhibitory avoidance (IA) and other behaviorally arousing tasks. Here, we investigate molecular correlates of IA consolidation in the two structures and their relation to NMDA receptors (NMDArs) and beta-adrenergic receptors (beta-ADrs). The separate posttraining administration of antagonists of NMDAr and beta-ADr to BLA and CA1 is amnesic. IA training is followed by an increase of the phosphorylation of calcium and calmodulin-dependent protein kinase II (CaMKII) and ERK2 in CA1 but only an increase of the phosphorylation of ERK2 in BLA. The changes are blocked by NMDAr antagonists but not beta-ADr antagonists in CA1, and they are blocked by beta-ADr but not NMDAr antagonists in BLA. In addition, the changes are accompanied by increased phosphorylation of tyrosine hydroxylase in BLA but not in CA1, suggesting that beta-AD modulation results from local catecholamine synthesis in the former but not in the latter structure. NMDAr blockers in CA1 do not alter the learning-induced neurochemical changes in BLA, and beta-ADr blockade in BLA does not hinder those in CA1. When put together with other data from the literature, the present findings suggest that CA1 and BLA play a role in consolidation, but they operate to an extent in parallel, suggesting that each is probably involved with different aspects of the task studied.

The role of the entorhinal cortex in extinction: influences of aging.

The entorhinal cortex is perhaps the area of the brain in which neurofibrillary tangles and amyloid plaques are first detectable in old age with or without mild cognitive impairment, and very particularly in Alzheimer's disease. It plays a key role in memory formation, retrieval, and extinction, as part of circuits that include the hippocampus, the amygdaloid nucleus, and several regions of the neocortex, in particular of the prefrontal cortex. Lesions or biochemical impairments of the entorhinal cortex hinder extinction. Microinfusion experiments have shown that glutamate NMDA receptors, calcium and calmodulin-dependent protein kinase II, and protein synthesis in the entorhinal cortex are involved in and required for extinction. Aging also hinders extinction; it is possible that its effect may be in part mediated by the entorhinal cortex.