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Changes in memory performance are one of the main symptoms of normal aging. The storage of similar experiences as different memories (ie. behavioral pattern separation), becomes less efficient as aging progresses. Studies have focused on hippocampus dependent spatial memories and their role in the aging related deficits in behavioral pattern separation (BPS) by targeting high similarity interference conditions. However, parahippocampal cortices such as the perirhinal cortex are also particularly vulnerable to aging. Middle age is thought to be the stage where mild mnemonic deficits begin to emerge. Therefore, a better understanding of the timing of the spatial and object domain memory impairment could shed light over how plasticity changes in the parahipocampal-hippocampal system affects mnemonic function in early aging. In the present work, we compared the performance of young and middle-aged rats in both spatial (spontaneous location recognition) and non-spatial (spontaneous object recognition) behavioral pattern separation tasks to understand the comparative progression of these deficits from early stages of aging. Moreover, we explored the impact of environmental enrichment (EE) as an intervention with important translational value. Although a bulk of studies have examined the contribution of EE for preventing age related memory decline in diverse cognitive domains, there is limited knowledge of how this intervention could specifically impact on BPS function in middle-aged animals. Here we evaluate the effects of EE as modulator of BPS, and its ability to revert the deficits caused by normal aging at early stages. We reveal a domain-dependent impairment in behavioral pattern separation in middle-aged rats, with spatial memories affected independently of the similarity of the experiences and object memories only affected when the stimuli are similar, an effect that could be linked to the higher interference seen in this group. Moreover, we found that EE significantly enhanced behavioral performance in middle-aged rats in the spatial and object domain, and this improvement is specific of the high similarity load condition. In conclusion, these results suggest that memory is differentially affected by aging in the object and spatial domains, but that BPS function is responsive to an EE intervention in a multidomain manner., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Miranda, Navas, Zanoni Saad, Piromalli Girado, Weisstaub and Bekinschtein.)

Labilization-reconsolidation, which relies on retrieval, has been considered an opportunity to attenuate the negative aspects of traumatic memories. A therapeutic strategy based on reconsolidation blockade is deemed more effective than current therapies relying on memory extinction. Nevertheless, extremely stressful memories frequently prove resistant to this process. Here, after inducing robust fear memory in mice through strong fear conditioning, we examined the possibility of rendering it susceptible to pharmacological modulation based on the degree of generalized fear (GF). To achieve this, we established an ordered gradient of GF, determined by the perceptual similarity between the associated context (CA) and non-associated contexts (CB, CC, CD, and CE) to the aversive event. We observed that as the exposure context became less similar to CA, the defensive pattern shifted from passive to active behaviors in both male and female mice. Subsequently, in conditioned animals, we administered propranolol after exposure to the different contexts (CA, CB, CC, CD or CE). In males, propranolol treatment resulted in reduced freezing time and enhanced risk assessment behaviors when administered following exposure to CA or CB, but not after CC, CD, or CE, compared to the control group. In females, a similar change in behavioral pattern was observed with propranolol administered after exposure to CC, but not after the other contexts. These results highlight the possibility of indirectly manipulating a robust contextual fear memory by controlling the level of generalization during recall. Additionally, it was demonstrated that the effect of propranolol on reconsolidation would not lead to a reduction in fear memory per se, but rather to its reorganization resulting in greater behavioral flexibility (from passive to active behaviors). Finally, from a clinical viewpoint, this would be of considerable relevance since following this strategy could make the treatment of psychiatric disorders associated with traumatic memory formation more effective and less stressful., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: The ability to separate similar experiences into differentiated representations is proposed to be based on a computational process called pattern separation, and it is one of the key characteristics of episodic memory. Although pattern separation has been mainly studied in the dentate gyrus of the hippocampus, this cognitive function if thought to take place also in other regions of the brain. The perirhinal cortex is important for the acquisition and storage of object memories, and in particular for object memory differentiation. The present study was devoted to investigating the importance of the cellular mechanism of endocytosis for object memory differentiation in the perirhinal cortex and its association with brain-derived neurotrophic factor, which was previously shown to be critical for the pattern separation mechanism in this structure., Methods: We used a modified version of the object recognition memory task and intracerebral delivery of a peptide (Tat-P4) into the perirhinal cortex to block endocytosis., Results: We found that endocytosis is necessary for pattern separation in the perirhinal cortex. We also provide evidence from a molecular disconnection experiment that BDNF and endocytosis-related mechanisms interact for memory discrimination in both male and female rats., Discussion: Our experiments suggest that BDNF and endocytosis are essential for consolidation of separate object memories and a part of a time-restricted, protein synthesis-dependent mechanism of memory stabilization in Prh during storage of object representations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Piromalli Girado, Miranda, Giachero, Weisstaub and Bekinschtein.)

Previous experiences can drive adaptive behavior based on different characteristics, including contextual ones. Indeed, contextual information can be used as a criterion to guide the recall of the most relevant memory trace and the inhibition of others. The medial Prefontal Cortex (mPFC) has been proposed as an area that plays a pivotal role in regulating the retrieval of memory traces in downstream regions. Also, we have shown that mPFC Serotonin 2a Receptors (5-HT2aR) modulates the retrieval of a contextually guided recognition memory task and modulates the retrieval and reconsolidation of memories in the Perirhinal Cortex (PRH). However, how the mPFC output mediated by the 5-HT2aR activity is modulating memory retrieval in the PRH is a question that remains unclear. To tackle this question, we analyzed neuronal activity in the PRH and mPFC, by measuring expression of the immediate early gene c-Fos. We combined behavioral, pharmacological and immunohistochemical techniques to examine how mPFC 5-HT2aR controls mPFC and the PRH activity. We found that blockade of mPFC 5-HT2aR increase the level of c-Fos expression in the PHR and that this increase correlates with animals' performance in the task. We also found an increase in c-Fos expression in the mPFC after mPFC 5-HT2aR blockade that does not correlate with the animals' behavioral response. However, these changes showed a significant correlation with those observed in the PRH. These results suggest that mPFC 5-HT2aR signaling may modulate the behavioral response during memory recall by controlling the neuronal activation in the PRH., (Copyright © 2022 IBRO. Published by Elsevier Ltd. All rights reserved.)

Mitochondria in neurons, in addition to their primary role in bioenergetics, also contribute to specialized functions, including regulation of synaptic transmission, Ca 2+ homeostasis, neuronal excitability, and stress adaptation. However, the factors that influence mitochondrial biogenesis and function in neurons remain poorly elucidated. Here, we identify an important role for serotonin (5-HT) as a regulator of mitochondrial biogenesis and function in rodent cortical neurons, via a 5-HT 2A receptor-mediated recruitment of the SIRT1-PGC-1α axis, which is relevant to the neuroprotective action of 5-HT. We found that 5-HT increased mitochondrial biogenesis, reflected through enhanced mtDNA levels, mitotracker staining, and expression of mitochondrial components. This resulted in higher mitochondrial respiratory capacity, oxidative phosphorylation (OXPHOS) efficiency, and a consequential increase in cellular ATP levels. Mechanistically, the effects of 5-HT were mediated via the 5-HT 2A receptor and master modulators of mitochondrial biogenesis, SIRT1 and PGC-1α. SIRT1 was required to mediate the effects of 5-HT on mitochondrial biogenesis and function in cortical neurons. In vivo studies revealed that 5-HT 2A receptor stimulation increased cortical mtDNA and ATP levels in a SIRT1-dependent manner. Direct infusion of 5-HT into the neocortex and chemogenetic activation of 5-HT neurons also resulted in enhanced mitochondrial biogenesis and function in vivo. In cortical neurons, 5-HT enhanced expression of antioxidant enzymes, decreased cellular reactive oxygen species, and exhibited neuroprotection against excitotoxic and oxidative stress, an effect that required SIRT1. These findings identify 5-HT as an upstream regulator of mitochondrial biogenesis and function in cortical neurons and implicate the mitochondrial effects of 5-HT in its neuroprotective action., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

Background: Acute treatment with the selective serotonin reuptake inhibitor (SSRI), fluoxetine (Flx), induces anxiety-like behavioral effects. The serotonin 2A receptor (5-HT 2A ) is implicated in the modulation of anxiety-like behavior, however its contribution to the anxiogenic effects of acute Flx remains unclear. Here, we examined the role of the 5-HT 2A receptor in the effects of acute Flx on anxiety-like behavior, serum corticosterone levels, neural activation and immediate early gene (IEG) expression in stress-responsive brain regions, using 5-HT 2A receptor knockout (5-HT 2A -/- ) mice of both sexes. Methods: 5-HT 2A -/- and wild-type (WT) male and female mice received a single administration of Flx or vehicle, and were examined for anxiety-like behavior, serum corticosterone levels, FBJ murine osteosarcoma viral oncogene homolog peptide (c-Fos) positive cell numbers in stress-responsive brain regions of the hypothalamus and prefrontal cortex (PFC), and PFC IEG expression. Results: The increased anxiety-like behavior and enhanced corticosterone levels evoked by acute Flx were unaltered in 5-HT 2A -/- mice of both sexes. 5-HT 2A -/- female mice exhibited a diminished neural activation in the hypothalamus in response to acute Flx. Further, 5-HT 2A -/- male, but not female, mice displayed altered baseline expression of several IEGs (brain-derived neurotrophic factor ( Bdnf ), Egr2, Egr4 , FBJ osteosarcoma gene ( Fos ), FBJ murine osteosarcoma viral oncogene homolog B ( Fosb ), Fos-like antigen 2 ( Fosl2 ), Homer scaffolding protein ( Homer ) 1-3 ( Homer1-3 ), Jun proto-oncogene ( Jun )) in the PFC. Conclusion: Our results indicate that the increased anxiety and serum corticosterone levels evoked by acute Flx are not influenced by 5-HT 2A receptor deficiency. However, the loss of function of the 5-HT 2A receptor alters the degree of neural activation of the paraventricular nucleus (PVN) of the hypothalamus in response to acute Flx, and baseline expression of several IEGs in the PFC in a sexually dimorphic manner., Competing Interests: The authors declare that there are no competing interests associated with the manuscript., (© 2019 The Author(s).)

Successful memory involves not only remembering information over time but also keeping memories distinct and less confusable. Discrimination of overlapping representations has been investigated in the dentate gyrus (DG) of the hippocampus and largely in the perirhinal cortex (Prh). In particular, the DG was shown to be important for discrimination of overlapping spatial memories and Prh was shown to be important for discrimination of overlapping object memories. In the present study, we used both a DG-dependent and a Prh-dependent task and manipulated the load of similarity between either spatial or object stimuli during information encoding. We showed that N-methyl-D-aspartate-type glutamate receptors (NMDAr) and BDNF participate of the same cellular network during consolidation of both overlapping object and spatial memories in the Prh and DG, respectively. This argues in favor of conserved cellular mechanisms across regions despite anatomical differences., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Chronic stress enhances risk for psychiatric disorders, and in animal models is known to evoke depression-like behavior accompanied by perturbed neurohormonal, metabolic, neuroarchitectural and transcriptional changes. Serotonergic neurotransmission, including serotonin 2A (5-HT 2A ) receptors, have been implicated in mediating specific aspects of stress-induced responses. Here we investigated the influence of chronic unpredictable stress (CUS) on depression-like behavior, serum metabolic measures, and gene expression in stress-associated neurocircuitry of the prefrontal cortex (PFC) and hippocampus in 5-HT 2A receptor knockout (5-[Formula: see text]) and wild-type mice of both sexes. While 5-[Formula: see text] male and female mice exhibited a baseline reduced anxiety-like state, this did not alter the onset or severity of behavioral despair during and at the cessation of CUS, indicating that these mice can develop stress-evoked depressive behavior. Analysis of metabolic parameters in serum revealed a CUS-evoked dyslipidemia, which was abrogated in 5-[Formula: see text] female mice with a hyperlipidemic baseline phenotype. 5-[Formula: see text] male mice in contrast did not exhibit such a baseline shift in their serum lipid profile. Specific stress-responsive genes ( Crh , Crhr1 , Nr3c1, and Nr3c2 ), trophic factors ( Bdnf , Igf1 ) and immediate early genes (IEGs) ( Arc , Fos , Fosb , Egr1-4 ) in the PFC and hippocampus were altered in 5-[Formula: see text] mice both under baseline and CUS conditions. Our results support a role for the 5-HT 2A receptor in specific metabolic and transcriptional, but not behavioral, consequences of CUS, and highlight that the contribution of the 5-HT 2A receptor to stress-evoked changes is sexually dimorphic.

Childhood obesity is the main nutritional and public health problem in Chile, being the principal causes, the increase in energy dense foods and the decline of physical activity. Interventions to prevent obesity at infancy are focused mainly in improving quality and quantity of dietary intake, without taking into account physical activity, which is expressed under two years of age, mainly by motor development. Some studies have proven that motor development at early age, may influence the ability to perform physical activity. Thus, infants scoring a lower motor development may have a greater risk of becoming obese. It isn’t know if childhood obesity causes lower motor development (given that children may have greater difficulty to move), or on the contrary, it is the lower ability to move, which increases the obesity risk. The objective of this manuscriptis analize the evidence regards the relation between breastfeeding, motor development and obesity in the childhood.To be able to understand this asocation and casual mecanism, it is important to develop stategys focused in early infancy to promote breastfeeding, healthy eating and early stimulation, starting in pediatric office.

Medial prefrontal cortex (mPFC) is essential for initial memory processing and expression but its involvement in persistent memory storage has seldom been studied. Using the hippocampus dependent inhibitory avoidance learning task and the hippocampus-independent conditioned taste aversion paradigm together with specific dopamine receptor agonists and antagonists we found that persistence but not formation of long-term aversive memories requires dopamine D1/D5 receptors activation in mPFC immediately after training and, depending on the task, between 6 and 12 h later. Our results indicate that besides its well-known participation in retrieval and early consolidation, mPFC also modulates the endurance of long-lasting aversive memories regardless of whether formation of the aversive mnemonic trace requires the participation of the hippocampus.

One of the challenges for memory researches is the study of the neurobiology of episodic memory which is defined by the integration of all the different components of experiences that support the conscious recollection of events. The features of episodic memory includes a particular object or person ("what"), the context in which the experience took place ("where") and the particular time at which the event occurred ("when"). Although episodic memory has been mainly studied in humans, there are many studies that demonstrate these features in non-human animals. Here, we summarize a set of studies that employ different versions of recognition memory tasks in animals to study the role of the medial prefrontal cortex in episodic memory., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The neocortex is thought to be a distributed learning system that gradually integrates semantic information into the initial mnemonic representation rapidly formed by the hippocampus after acquisition. Nevertheless, an emerging view suggests that some cortical regions, in particular the medial prefrontal cortex (mPFC), may also have a role during the initial steps of memory consolidation as well as in the recall of recent memories. Here, we show that mPFC plays a critical role during the first few hours of inhibitory avoidance memory consolidation and is necessary for the normal retrieval of both recent and remote memories, supporting the idea that involvement of neocortical areas in memory processing is not restricted to the late post-training consolidation phase., (Copyright © 2013 Elsevier Inc. All rights reserved.)

We have performed a systematic mutagenesis of three hydrophobic rings (17', 13' and 9') within transmembrane region (TM) 2 of the alpha9alpha10 nicotinic cholinergic receptor (nAChR) to a hydrophilic (threonine) residue and compared the properties of mutant receptors reconstituted in Xenopus laevis oocytes. Phenotypic changes in alpha9alpha10 mutant receptors were evidenced by a decrease in the desensitization rate, an increase in both the EC(50) for ACh as well as the efficacy of partial agonists and the reduction of the allosteric modulation by extracellular Ca(2+). Mutated receptors exhibited spontaneous openings and, at the single-channel level, an increased apparent mean open time with no major changes in channel conductance, thus suggesting an increase in gating of the channel as the underlying mechanism. Overall, the degrees of the phenotypes of mutant receptors were more overt in the case of the centrally located V13'T mutant. Based on the atomic model of the pore of the electric organ of the Torpedo ray, we can propose that the interactions of side chains at positions 13' and 9' are key ones in creating an energetic barrier to ion permeation. In spite of the fact that the roles of the TM2 residues are mostly conserved in the distant alpha9alpha10 member of the nAChR family, their mechanistic contributions to channel gating show significant differences when compared to other nAChRs. These differences might be originated from slight differential intramolecular rearrangements during gating for the different receptors and might lead each nAChR to be in tune with their physiological roles.

Most neuropharmacological agents and many drugs of abuse modulate the activity of heptahelical G-protein-coupled receptors. Although the effects of these ligands result from changes in cellular signaling, their neurobehavioral activity may not correlate with results of in vitro signal transduction assays. 5-Hydroxytryptamine 2A receptor (5-HT2AR) partial agonists that have similar pharmacological profiles differ in the behavioral responses they elicit. In vitro studies suggest that different agonists acting at the same receptor may establish distinct patterns of signal transduction. Testing this hypothesis in the brain requires a global signal transduction assay that is applicable in vivo. To distinguish the cellular effects of the different 5-HT2AR agonists, we developed an assay for global signal transduction on the basis of high throughput quantification of rapidly modulated transcripts. Study of the responses to agonists in human embryonic kidney 293 cells stably expressing 5-HT2ARs demonstrated that each agonist elicits a distinct transcriptome fingerprint. We therefore studied behavioral and cortical signal transduction responses in wild-type and 5-HT2AR null-mutant mice. The hallucinogenic chemicals (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) and lysergic acid diethylamide (LSD) stimulated a head-twitch behavioral response that was not observed with the nonhallucinogenic lisuride hydrogen maleate (LHM) and was absent in receptor null-mutant mice. We also found that DOI, LSD, and LHM each induced distinct transcriptome fingerprints in somatosensory cortex that were absent in 5-HT2AR null-mutants. Moreover, DOI and LSD showed similarities in the transcriptome fingerprints obtained that were not observed with the behaviorally inactive drug LHM. Our results demonstrate that chemicals acting at the 5-HT2AR induce specific cellular response patterns in vivo that are reflected in unique changes in the somatosensory cortex transcriptome.

Various chronic antidepressant treatments increase adult hippocampal neurogenesis, but the functional importance of this phenomenon remains unclear. Here, using genetic and radiological methods, we show that disrupting antidepressant-induced neurogenesis blocks behavioral responses to antidepressants. Serotonin 1A receptor null mice were insensitive to the neurogenic and behavioral effects of fluoxetine, a serotonin selective reuptake inhibitor. X-irradiation of a restricted region of mouse brain containing the hippocampus prevented the neurogenic and behavioral effects of two classes of antidepressants. These findings suggest that the behavioral effects of chronic antidepressants may be mediated by the stimulation of neurogenesis in the hippocampus.

Serotonin (5-HT) modulates numerous processes in the central nervous system that are relevant to neuropsychiatric function and dysfunction. It exerts significant effects on anxiety, mood, impulsivity, sleep, ingestive behavior, reward systems, and psychosis. Serotonergic dysfunction has been implicated in several psychiatric conditions but efforts to more clearly understand the mechanisms of this influence have been hampered by the complexity of this system at the receptor level. There are at least 14 distinct receptors that mediate the effects of 5-HT as well as several enzymes that control its synthesis and metabolism. Pharmacologic agents that target specific receptors have provided clues regarding the function of these receptors in the human brain. 5-HT is also an important modulator of neural development and several groups have employed a genetic strategy relevant to behavior. Several inactivation mutations of specific 5-HT receptors have been generated producing interesting behavioral phenotypes related to anxiety, depression, drug abuse, psychosis, and cognition. In many cases, knockout mice have been used to confirm what has already been suspected based on pharmacologic studies. In other instances, mutations have demonstrated new functions of serotonergic genes in development and behavior.

The native cholinergic receptor that mediates synaptic transmission between olivocochlear fibers and outer hair cells of the cochlea is permeable to Ca(2+) and is thought to be composed of both the alpha 9 and the alpha 10 cholinergic nicotinic subunits. The aim of the present work was to study the permeability of the recombinant alpha 9 alpha 10 nicotinic acetylcholine receptor to Ca(2+), Ba(2+) and Mg(2+) and its modulation by these divalent cations. Experiments were performed, by the two-electrode voltage-clamp technique, in Xenopus laevis oocytes injected with alpha 9 and alpha 10 cRNA. The relative divalent to monovalent cation permeability was high ( approximately 10) for Ca(2+), Ba(2+) and Mg(2+). Currents evoked by acetylcholine (ACh) were potentiated by either Ca(2+) or Ba(2+) up to 500 microM but were blocked by higher concentrations of these cations. Potentiation by Ca(2+) was voltage-independent, whereas blockage was stronger at hyperpolarized than at depolarized potentials. Mg(2+) did not potentiate but it blocked ACh-evoked currents (IC(50)=0.38 mM). In the absence of Ca(2+), the EC(50) for ACh was higher (48 microM) than that obtained with 1.8 mM Ca(2+) (14.3 microM), suggesting that potentiation by Ca(2+) involves changes in the apparent affinity of the alpha 9 alpha 10 receptor for ACh.