Underlying Mechanisms of the Protective Effects of Lifestyle Factors On Age-Related Diseases.

The rise in life expectancy has significantly increased the occurrence of age-related chronic diseases, leading to escalating expenses for both society and individuals. Among the main factors influencing health and lifespan, lifestyle takes a forefront position. Specifically, nutrition, mental activity, and physical exercise influence the molecular and functional mechanisms that contribute to the prevention of major age-related diseases. Gaining deeper insights into the mechanisms that drive the positive effects of healthy lifestyles is valuable for creating interventions to prevent or postpone the development of chronic degenerative diseases. This review summarizes the main mechanisms that underlie the positive effect of lifestyle factors in counteracting the major age-related diseases involving brain health, musculoskeletal function, cancer, frailty, and cardiovascular diseases, among others. This knowledge will help to identify high-risk populations for targeted intervention trials and discover new biomarkers associated with healthy aging.

Early-life and chronic exposure to high-fat diet alters noradrenergic and glutamatergic neurotransmission in the male rat amygdala and hippocampus under cognitive challenges.

Childhood obesity increases the risk of health and cognitive disorders in adulthood. Consuming high-fat diets (HFD) during critical neurodevelopmental periods, like childhood, impairs cognition and memory in humans and animals, affecting the function and connectivity of brain structures related to emotional memory. However, the underlying mechanisms of such phenomena need to be better understood. This study aimed to investigate the neurochemical profile of the amygdala and hippocampus, brain structures involved in emotional memory, during the acquisition of conditioned odor aversion in male rats that consumed a HFD from weaning to adulthood. The rats gained weight, experienced metabolic changes, and reduced insulin sensitivity and glucose tolerance. Rats showed enhanced odor aversion memory, contrary to the expected cognitive impairments. This memory enhancement was accompanied by increased noradrenergic and glutamatergic neurotransmission in the amygdala and hippocampus. Importantly, this upregulation was specific to stimuli exposure, as basal neurotransmitter levels remained unaltered by the HFD. Our results suggest that HFD modifies cognitive function by altering neurochemical signaling, in this case, upregulating neurotransmitter levels rendering a stronger memory trace, demonstrating that metabolic dysfunctions do not only trigger exclusively detrimental plasticity processes but also render enhanced plastic effects depending on the type of information.

Transforming experiences: Neurobiology of memory updating/editing.

Long-term memory is achieved through a consolidation process where structural and molecular changes integrate information into a stable memory. However, environmental conditions constantly change, and organisms must adapt their behavior by updating their memories, providing dynamic flexibility for adaptive responses. Consequently, novel stimulation/experiences can be integrated during memory retrieval; where consolidated memories are updated by a dynamic process after the appearance of a prediction error or by the exposure to new information, generating edited memories. This review will discuss the neurobiological systems involved in memory updating including recognition memory and emotional memories. In this regard, we will review the salient and emotional experiences that promote the gradual shifting from displeasure to pleasure (or vice versa), leading to hedonic or aversive responses, throughout memory updating. Finally, we will discuss evidence regarding memory updating and its potential clinical implication in drug addiction, phobias, and post-traumatic stress disorder.

Dopamine activity on the perceptual salience for recognition memory.

To survive, animals must recognize relevant stimuli and distinguish them from inconspicuous information. Usually, the properties of the stimuli, such as intensity, duration, frequency, and novelty, among others, determine the salience of the stimulus. However, previously learned experiences also facilitate the perception and processing of information to establish their salience. Here, we propose "perceptual salience" to define how memory mediates the integration of inconspicuous stimuli into a relevant memory trace without apparently altering the recognition of the physical attributes or valence, enabling the detection of stimuli changes in future encounters. The sense of familiarity is essential for successful recognition memory; in general, familiarization allows the transition of labeling a stimulus from the novel (salient) to the familiar (non-salient). The novel object recognition (NOR) and object location recognition (OLRM) memory paradigms represent experimental models of recognition memory that allow us to study the neurobiological mechanisms involved in episodic memory. The catecholaminergic system has been of vital interest due to its role in several aspects of recognition memory. This review will discuss the evidence that indicates changes in dopaminergic activity during exposure to novel objects or places, promoting the consolidation and persistence of memory. We will discuss the relationship between dopaminergic activity and perceptual salience of stimuli enabling learning and consolidation processes necessary for the novel-familiar transition. Finally, we will describe the effect of dopaminergic deregulation observed in some pathologies and its impact on recognition memory.

Voluntary physical activity improves spatial and recognition memory deficits induced by post-weaning chronic exposure to a high-fat diet.

Childhood and adolescent exposure to obesogenic environments has contributed to the development of several health disorders, including neurocognitive impairment. Adolescence is a critical neurodevelopmental window highly influenced by environmental factors that affect brain function until adulthood. Post-weaning chronic exposure to a high-fat diet (HFD) adversely affects memory performance; physical activity is one approach to coping with these dysfunctions. Previous studies indicate that voluntary exercise prevents HFD's detrimental effects on memory; however, it remains to evaluate whether it has a remedial/therapeutical effect when introduced after a long-term HFD exposure. This study was conducted on a diet-induced obesity mice model over six months. After three months of HFD exposure (without interrupting the diet) access to voluntary physical activity was provided. HFD produced weight gain, increased adiposity, and impaired glucose tolerance. Voluntary physical exercise ameliorated glucose tolerance and halted weight gain and fat accumulation. Additionally, physical activity mitigated HFD-induced spatial and recognition memory impairments. Our data indicate that voluntary physical exercise starting after several months of periadolescent HFD exposure reverses metabolic and cognitive alterations demonstrating that voluntary exercise, in addition to its known preventive effect, also has a restorative impact on metabolism and cognition dysfunctions associated with obesity.

Serum Levels of Glial Fibrillary Acidic Protein Association with Cognitive Impairment and Type 2 Diabetes.

BACKGROUND: Peripheral biomarkers associated with neurocognitive disorders (NCD) have been evaluated in an attempt to improve diagnosis and early detection and potentially even prevent them. Along with increasing age, type 2 diabetes (T2D) increases the risk of central nervous system disorders and cognitive impairment due to the loss of synaptic function. Central damage triggers an astroglial response, increasing the expression of glial fibrillary acidic protein (GFAP), which can be found peripherally when the blood-brain barrier is compromised. AIM OF THE STUDY: To evaluate the value of GFAP as a peripheral biomarker of central dysfunction. METHODS: Serum levels of GFAP were compared between cases of NCD (n = 69) and age-matched controls (n = 69), analyzing the influence of diabetes as contributing factor. RESULTS: We found higher levels of serum GFAP in subjects with NCD compared with the control group (p <0.0001). The receiver operating characteristic (ROC) curve using the GFAP levels showed 65.22% sensitivity and 71.01% specificity (AUC = 0.7608), indicating good performance in the classification of controls and NCD patients. Logistic regression indicated a positive predictive power of 67.50% considering T2D status; adding GFAP levels, the predictive power rises to 71.93%. GFAP levels and T2D could be considered good predictors of NCD risk. CONCLUSIONS: Our findings open the possibility that peripheral GFAP could be used as an objective measurement related, under certain conditions, to central damage; thereby serving as a follow-up marker to refer diabetic patients for appropriate neurological evaluation, which could offer a low cost, minimally invasive strategy to improve the assessment of cognitive affectation and subsequent treatment.

Cognitive Impairment in Alzheimer's and Metabolic Diseases: A Catecholaminergic Hypothesis.

Catecholaminergic transmission plays an essential role in both physiological and pathological cognitive functions. Plastic changes subserving learning and memory processes are highly dependent on catecholaminergic activity, altering their function and impacting cognition. This review assesses changes in the dopaminergic and norepinephrine systems as part of the mechanisms underlying cognitive impairment in Alzheimer's disease as associated with metabolic dysfunctions such as type 2 diabetes, metabolic syndrome, and neuroinflammation and peripheral inflammation. Understanding the role of catecholaminergic systems in these conditions is relevant for identifying etiological factors that could advance diagnostic and therapeutic approaches for ameliorating cognitive alterations, disease onset, and progression.

Cortical neurochemical signaling of gustatory stimuli and their visceral consequences during the acquisition and consolidation of taste aversion memory.

The insular cortex (IC) has a crucial role in taste recognition memory, including conditioned taste aversion (CTA). CTA is a learning paradigm in which a novel taste stimulus (CS) is associated with gastric malaise (US), inducing aversion to the CS in future encounters. The role of the IC in CTA memory formation has been extensively studied. However, the functional significance of neurotransmitter release during the presentation of taste stimuli and gastric malaise-inducing agents remains unclear. Using microdialysis in free-moving animals, we evaluated simultaneous changes in glutamate, norepinephrine and dopamine release in response to the presentation of an innate appetitive or aversive gustatory novel stimulus, as well as after i.p. administration of isotonic or hypertonic gastric malaise-inducing solutions. Our results demonstrate that the presentation of novel stimuli, regardless of their innate valence, induces an elevation of norepinephrine and dopamine. Administration of a gastric malaise inducing agent (LiCl) promotes an elevation of glutamate regardless of its concentration. In comparison, norepinephrine release is related to the LiCl concentration and its equimolar NaCl control. Additionally, we evaluated their functional role on short and long-term taste aversion memory. Results indicate that the blockade of noradrenergic ß1,2 receptors in the IC spares CTA acquisition and memory consolidation. In contrast, blockade of dopamine D1/D5 receptors impaired CTA consolidation, whereas the NMDA receptor blockade impedes both acquisition and consolidation of CTA. These results suggest that dopaminergic and noradrenergic release are related to the salience of conditioned taste stimuli. However, only cortical D1/D5 dopaminergic activity, but not the noradrenergic ß1,2 activity, is involved in the acquisition and consolidation of taste memory formation. Additionally, glutamatergic activity signals visceral distress caused by LiCl administration and activates NMDA receptors necessary for the acquisition and consolidation of long-lasting taste aversion memory.

Catecholaminergic stimulation restores high-sucrose diet-induced hippocampal dysfunction.

Increasing evidence suggests that long-term consumption of high-caloric diets increases the risk of developing cognitive dysfunctions. In the present study, we assessed the catecholaminergic activity in the hippocampus as a modulatory mechanism that is altered in rats exposed to six months of a high-sucrose diet (HSD). Male Wistar rats fed with this diet developed a metabolic disorder and showed impaired spatial memory in both water maze and object location memory (OLM) tasks. Intrahippocampal free-movement microdialysis showed a diminished dopaminergic and noradrenergic response to object exploration during OLM acquisition compared to rats fed with normal diet. In addition, electrophysiological results revealed an impaired long-term potentiation (LTP) of the perforant to dentate gyrus pathway in rats exposed to a HSD. Local administration of nomifensine, a catecholaminergic reuptake inhibitor, prior to OLM acquisition or LTP induction, improved long-term memory and electrophysiological responses, respectively. These results suggest that chronic exposure to HSD induces a hippocampal deterioration which impacts on cognitive and neural plasticity events negatively; these impairments can be ameliorated by increasing or restituting the affected catecholaminergic activity.

Artificial taste avoidance memory induced by coactivation of NMDA and ß-adrenergic receptors in the amygdala.

The association between a taste and gastric malaise allows animals to avoid the ingestion of potentially toxic food. This association has been termed conditioned taste aversion (CTA) and relies on the activity of key brain structures such as the amygdala and the insular cortex. The establishment of this gustatory-avoidance memory is related to glutamatergic and noradrenergic activity within the amygdala during two crucial events: gastric malaise (unconditioned stimulus, US) and the post-acquisition spontaneous activity related to the association of both stimuli. To understand the functional implications of these neurochemical changes on avoidance memory formation, we assessed the effects of pharmacological stimulation of ß-adrenergic and glutamatergic NMDA receptors through the administration of a mixture of L-homocysteic acid and isoproterenol into the amygdala after saccharin exposure on specific times to emulate the US and post-acquisition local signals that would be occurring naturally under CTA training. Our results show that activation of NMDA and ß-adrenergic receptors generated a long-term avoidance response to saccharin, like a naturally induced rejection with LiCl. Moreover, the behavioral outcome was accompanied by changes in glutamate, norepinephrine and dopamine levels within the insular cortex, analogous to those displayed during memory retrieval of taste aversion memory. Therefore, we suggest that taste avoidance memory can be induced artificially through the emulation of specific amygdalar neurochemical signals, promoting changes in the amygdala-insular cortex circuit enabling memory establishment.

Differential requirement of de novo Arc protein synthesis in the insular cortex and the amygdala for safe and aversive taste long-term memory formation.

Several immediate early genes products are known to be involved in the facilitation of structural and functional modifications at distinct synapses activated through experience. The IEG-encoded protein Arc (activity regulated cytoskeletal-associated protein) has been widely implicated in long-term memory formation and stabilization. In this study, we sought to evaluate a possible role for de novo Arc protein synthesis in the insular cortex (IC) and in the amygdala (AMY) during long-term taste memory formation. We found that acute inhibition of Arc protein synthesis through the infusion of antisense oligonucleotides administered in the IC before a novel taste presentation, affected consolidation of a safe taste memory trace (ST) but spared consolidation of conditioned taste aversion (CTA). Conversely, blocking Arc synthesis within the AMY impaired CTA consolidation but had no effect on ST long-term memory formation. Our results suggest that Arc-dependent plasticity during taste learning is required within distinct structures of the medial temporal lobe, depending on the emotional valence of the memory trace.

Palatable Hyper-Caloric Foods Impact on Neuronal Plasticity.

Neural plasticity is an intrinsic and essential characteristic of the nervous system that allows animals "self-tuning" to adapt to their environment over their lifetime. Activity-dependent synaptic plasticity in the central nervous system is a form of neural plasticity that underlies learning and memory formation, as well as long-lasting, environmentally-induced maladaptive behaviors, such as drug addiction and overeating of palatable hyper-caloric (PHc) food. In western societies, the abundance of PHc foods has caused a dramatic increase in the incidence of overweight/obesity and related disorders. To this regard, it has been suggested that increased adiposity may be caused at least in part by behavioral changes in the affected individuals that are induced by the chronic consumption of PHc foods; some authors have even drawn attention to the similarity that exists between over-indulgent eating and drug addiction. Long-term misuse of certain dietary components has also been linked to chronic neuroimmune maladaptation that may predispose individuals to neurodegenerative conditions such as Alzheimer's disease. In this review article, we discuss recent evidence that shows how consumption of PHc food can cause maladaptive neural plasticity that converts short-term ingestive drives into compulsive behaviors. We also discuss the neural mechanisms of how chronic consumption of PHc foods may alter brain function and lead to cognitive impairments, focusing on prenatal, childhood and adolescence as vulnerable neurodevelopmental stages to dietary environmental insults. Finally, we outline a societal agenda for harnessing permissive obesogenic environments.

Memory trace reactivation and behavioral response during retrieval are differentially modulated by amygdalar glutamate receptors activity: interaction between amygdala and insular cortex.

The insular cortex (IC) is required for conditioned taste aversion (CTA) retrieval. However, it remains unknown which cortical neurotransmitters levels are modified upon CTA retrieval. Using in vivo microdialysis, we observed that there were clear elevations in extracellular glutamate, norepinephrine, and dopamine in and around the center of the gustatory zone of the IC during CTA retrieval. Additionally, it has been reported that the amygdala-IC interaction is highly involved in CTA memory establishment. Therefore, we evaluated the effects of infusions of an AMPA receptor antagonist (CNQX) and a NMDA receptor antagonist (APV) into the amygdala on CTA retrieval and IC neurotransmitter levels. Infusion of APV into the amygdala impaired glutamate augmentation within the IC, whereas dopamine and norepinephrine levels augmentation persisted and a reliable CTA expression was observed. Conversely, CNQX infusion into the amygdala impaired the aversion response, as well as norepinephrine and dopamine augmentations in the IC. Interestingly, CNQX infusion did not affect glutamate elevation in the IC. To evaluate the functional meaning of neurotransmitters elevations within the IC on CTA response, we infused specific antagonists for the AMPA, NMDA, D1, and ß-adrenergic receptor before retrieval. Results showed that activation of AMPA, D1, and ß-adrenergic receptors is necessary for CTA expression, whereas NMDA receptors are not involved in the aversion response.

Dopaminergic neurotransmission dysfunction induced by amyloid-ß transforms cortical long-term potentiation into long-term depression and produces memory impairment.

Alzheimer's disease (AD) is a neurodegenerative condition manifested by synaptic dysfunction and memory loss, but the mechanisms underlying synaptic failure are not entirely understood. Although dopamine is a key modulator of synaptic plasticity, dopaminergic neurotransmission dysfunction in AD has mostly been associated to noncognitive symptoms. Thus, we aimed to study the relationship between dopaminergic neurotransmission and synaptic plasticity in AD models. We used a transgenic model of AD (triple-transgenic mouse model of AD) and the administration of exogenous amyloid-ß (Aß) oligomers into wild type mice. We found that Aß decreased cortical dopamine levels and converted in vivo long-term potentiation (LTP) into long-term depression (LTD) after high-frequency stimulation delivered at basolateral amygdaloid nucleus-insular cortex projection, which led to impaired recognition memory. Remarkably, increasing cortical dopamine and norepinephrine levels rescued both high-frequency stimulation -induced LTP and memory, whereas depletion of catecholaminergic levels mimicked the Aß-induced shift from LTP to LTD. Our results suggest that Aß-induced dopamine depletion is a core mechanism underlying the early synaptopathy and memory alterations observed in AD models and acts by modifying the threshold for the induction of cortical LTP and/or LTD.

Differential involvement of glutamatergic and catecholaminergic activity within the amygdala during taste aversion retrieval on memory expression and updating.

During memory retrieval, consolidated memories are expressed and destabilized in order to maintain or update information through a memory reconsolidation process. Despite the key role of the amygdala during memory acquistion and consolidation, the participation of neurotransmitter signals in memory retrieval is poorly understood. Hence, we used conditioned taste aversion and in vivo microdialysis to evaluate changes in glutamate, norepinephrine and dopamine concentrations within the amygdala during memory retrieval. We observed that exposure to an aversive-conditioned stimulus induced an augmentation in glutamate, norepinephrine and dopamine levels within the amygdala, while exposure to a familiar and safe stimulus did not induce changes in these neurotransmitters levels. Also, we evaluated the amygdalar blockade of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-d-aspartate (NMDA), ß-adrenergic and dopamine D1 receptors in memory retrieval and updating. Results showed that during retrieval, behavioural expression was impaired by intra-amygdalar blockade of AMPA and ß-adrenergic receptors, whereas NMDA, D1 and ß-adrenergic receptors blockade hindered memory updating. In summary, during conditioned taste aversion retrieval there was an increase in the extracellular levels of glutamate, norepinephrine and dopamine within the amygdala, and their receptors activity were differentially involved in the behavioural expression and memory updating during retrieval.

New Insights on Retrieval-Induced and Ongoing Memory Consolidation: Lessons from Arc.

The mainstream view on the neurobiological mechanisms underlying memory formation states that memory traces reside on the network of cells activated during initial acquisition that becomes active again upon retrieval (reactivation). These activation and reactivation processes have been called "conjunctive trace." This process implies that singular molecular events must occur during acquisition, strengthening the connection between the implicated cells whose synchronous activity must underlie subsequent reactivations. The strongest experimental support for the conjunctive trace model comes from the study of immediate early genes such as c-fos, zif268, and activity-regulated cytoskeletal-associated protein. The expressions of these genes are reliably induced by behaviorally relevant neuronal activity and their products often play a central role in long-term memory formation. In this review, we propose that the peculiar characteristics of Arc protein, such as its optimal expression after ongoing experience or familiar behavior, together with its versatile and central functions in synaptic plasticity could explain how familiarization and recognition memories are stored and preserved in the mammalian brain.

Role of glutamate receptors of central and basolateral amygdala nuclei on retrieval and reconsolidation of taste aversive memory.

There are a number of experiments showing an important involvement of amygdala N-methyl-d-aspartate (NMDA) glutamate receptors on consolidation of conditioned taste aversion (CTA) memory. Interestingly, recent evidence has shown that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors are particularly involved in CTA retrieval. Memory reconsolidation has been proposed as a destabilization and re-stabilization process induced by memory reactivation. We have recently suggested that reconsolidation could be enabled in the absence of retrieval. Hence, we decided to analyze the participation of AMPA and NMDA receptors of the central (CeA) and basolateral amygdala (BLA) in CTA memory retrieval and reconsolidation. To do so, we tested whether administrations of an AMPA receptor blocker (NBQX) or an NMDA receptor blocker (APV) 15 min before a second acquisition trial could have effects on taste aversion. We found that administration of NBQX in the BLA blocked retrieval, whereas APV blocked reconsolidation in the BLA, and consolidation in the CeA. When we administered both NBQX and APV into the BLA before the second acquisition trial, results showed impairment of both retrieval and reconsolidation. These results further support the idea that reconsolidation is independent of retrieval, since retrieval blockade in the BLA did not impair memory reconsolidation. These results suggest that glutamate receptors have different participation on retrieval and reconsolidation of CTA and further support the hypothesis that these two processes could be independent.

Interplay of amygdala and insular cortex during and after associative taste aversion memory formation.

The formation and storage of aversively motivated memories is based on plastic changes within the amygdala and other brain structures that are modulated by its activity. One of these structures is the insular cortex,which integrates environmental and interoceptive information such that memory traces can be efficient and rapidly stored. A great example of an aversively motivated learning is the taste aversion paradigm, which involves several changes at the cellular level of the amygdala and the insular cortex in order to be acquired and consolidated.So far, the interplay of these structures was described in terms of their participation during exposure to the stimuli to be associated; however, because of the cellular properties and interconnections between them, their functional interplay may go beyond the acquisition stage and the learning experience might trigger an ongoing engagement of amygdala-insular cortex reactivations in order to store the information.