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.

Paradoxical Boosting of Weak and Strong Spatial Memories by Hippocampal Dopamine Uncaging.

The ability to remember changes in the surroundings is fundamental for daily life. It has been proposed that novel events producing dopamine release in the hippocampal CA1 region could modulate spatial memory formation. However, the role of hippocampal dopamine increase on weak or strong spatial memories remains unclear. We show that male mice exploring two objects located in a familiar environment for 5 min created a short-term memory (weak) that cannot be retrieved 1 d later, whereas 10 min exploration created a long-term memory (strong) that can be retrieved 1 d later. Remarkably, hippocampal dopamine elevation during the encoding of weak object location memories (OLMs) allowed their retrieval 1 d later but dopamine elevation during the encoding of strong OLMs promoted the preference for a familiar object location over a novel object location after 24 h. Moreover, dopamine uncaging after the encoding of OLMs did not have effect on weak memories whereas on strong memories diminished the exploration of the novel object location. Additionally, hippocampal dopamine elevation during the retrieval of OLMs did not allow the recovery of weak memories and did not affect the retrieval of strong memory traces. Finally, dopamine elevation increased hippocampal theta oscillations, indicating that dopamine promotes the recurrent activation of specific groups of neurons. Our experiments demonstrate that hippocampal dopaminergic modulation during the encoding of OLMs depends on memory strength indicating that hyperdopaminergic levels that enhance weak experiences could compromise the normal storage of strong memories.

The anterior insula and its projection to amygdala nuclei modulate the abstinence-exacerbated expression of conditioned place preference.

RATIONALE: Relapse into substance use is often triggered by exposure to drug-related environmental cues. The magnitude of drug seeking depends on the duration of abstinence, a phenomenon known as the incubation of drug craving. Clinical and preclinical research shows that the insular cortex is involved in substance use disorders and cue-induced drug seeking. However, the role of the insula on memory retrieval and motivational integration for cue-elicited drug seeking remains to be determined. OBJECTIVES: We investigated the role of the anterior insular cortex (aIC) and its glutamatergic projection to amygdala nuclei (aIC-AMY) on the expression of conditioned place preference (CPP) during early and late abstinence. METHODS: Male adult C57BL/6J mice underwent amphetamine-induced CPP, and their preference was tested following 1 or 14 days of abstinence. aIC and aIC-AMY functional role in CPP expression was assessed at both abstinence periods by employing optogenetic silencing and behavioral pharmacology. RESULTS: Compared to a single day, an exacerbated preference for the amphetamine-paired context was observed after 14 days of abstinence. Photoinhibition of either aIC or aIC-AMY projection reduced CPP expression following late but not early abstinence. Similarly, the antagonism of aIC NMDA receptors reduced CPP expression after 14 days of abstinence but not 1 day. CONCLUSIONS: These results suggest that aIC and its glutamatergic output to amygdala nuclei constitute critical neurobiological substrates mediating enhanced motivational cue reactivity during the incubation of amphetamine craving rather than contextual memory recall. Moreover, cortical NMDA receptor signaling may become sensitized during abstinence, ultimately modulating disproportioned drug seeking.

Top-down circuitry from the anterior insular cortex to VTA dopamine neurons modulates reward-related memory.

The insular cortex (IC) has been linked to the processing of interoceptive and exteroceptive signals associated with addictive behavior. However, whether the IC modulates the acquisition of drug-related affective states by direct top-down connectivity with ventral tegmental area (VTA) dopamine neurons is unknown. We found that photostimulation of VTA terminals of the anterior insular cortex (aIC) induces rewarding contextual memory, modulates VTA activity, and triggers dopamine release within the VTA. Employing neuronal recordings and neurochemical and transsynaptic tagging techniques, we disclose the functional top-down organization tagging the aIC pre-synaptic neuronal bodies and identifying VTA recipient neurons. Furthermore, systemic administration of amphetamine altered the VTA excitability of neurons modulated by the aIC projection, where photoactivation enhances, whereas photoinhibition impairs, a contextual rewarding behavior. Our study reveals a key circuit involved in developing and retaining drug reward-related contextual memory, providing insight into the neurobiological basis of addictive behavior and helping develop therapeutic addiction strategies.

Synergistic photoactivation of VTA-catecholaminergic and BLA-glutamatergic projections induces long-term potentiation in the insular cortex.

The presentation of novel stimuli induces a reliable dopamine release in the insular cortex (IC) from the ventral tegmental area (VTA). The novel stimuli could be associated with motivational and emotional signals induced by cortical glutamate release from the basolateral amygdala (BLA). Dopamine and glutamate are essential for acquiring and maintaining behavioral tasks, including visual and taste recognition memories. In this study, we hypothesize that the simultaneous activation of dopaminergic and glutamatergic projections to the neocortex can underlie synaptic plasticity. High-frequency stimulation of the BLA-IC circuit has demonstrated a reliable long-term potentiation (LTP), a widely acknowledged synaptic plasticity that underlies memory consolidation. Therefore, the concurrent optogenetic stimulation of the insula's glutamatergic and dopaminergic terminal fibers would induce reliable LTP. Our results confirmed that combined photostimulation of the VTA and BLA projections to the IC induces a slow-onset LTP. We also found that optogenetically-induced LTP in the IC relies on both glutamatergic NMDA receptors and dopaminergic D1/D5 receptors, suggesting that the combined effects of these neurotransmitters can trigger synaptic plasticity in the neocortex. Overall, our findings provide compelling evidence supporting the essential role of both dopaminergic and glutamatergic projections in modulating synaptic plasticity within the IC. Furthermore, our results suggest that the synergistic actions of these projections have a pivotal influence on the formation of motivational memories.

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.

Salience to remember: VTA-IC dopaminergic pathway activity is necessary for object recognition memory formation.

Previous studies have shown that dopaminergic activity modulates the salience of novel stimuli enabling the formation of recognition memories. In this work, we hypothesize that dopamine released into the insular cortex (IC) from the ventral tegmental area (VTA) inputs enables the acquisition to consolidate object recognition memory. It has been reported that short training produces weak recognition memories; on the contrary, longer training produces lasting and robust recognition memories. Using a Cre-recombinase under the tyrosine hydroxylase (TH+) promoter mouse model, we photostimulated the VTA-IC dopaminergic pathway during short training or photoinhibited the same pathway during long training while mice explored objects. Our results showed that the photostimulation of the VTA-IC pathway during a short training enables the acquisition of recognition memory. Conversely, photoinhibition of the same pathway during a long training prevents the acquisition of recognition memory. Interestingly, the exploration time of the objects under photoinhibition or photostimulation of the dopaminergic VTA-IC pathway was not altered. Significantly, this enhancement of acquisition of the object recognition memory through the photostimulation of the VTA dopaminergic neurons could be impaired by the blockage of the D1-like receptors into the IC, either before or after the photostimulation. Altogether, our results suggest that dopamine released by the VTA is required during the acquisition to consolidate the object recognition memory through D1-like receptors into the IC without affecting the activity or the motivation to explore objects.

Inhibition of hippocampal palmitoyl acyltransferase activity impairs spatial learning and memory consolidation.

Protein palmitoylation regulates trafficking, mobilization, localization, interaction, and distribution of proteins through the palmitoyl acyltransferases (PATs) enzymes. Protein palmitoylation controls rapid and dynamic changes of the synaptic architecture that modifies the efficiency and strength of synaptic connections, a fundamental mechanism to generate stable and long-lasting memory traces. Although protein palmitoylation in functional synaptic plasticity has been widely described, its role in learning and memory processes is poorly understood. In this work, we found that PATs inhibition into the hippocampus before and after the training of Morris water maze (MWM) and object location memory (OLM) impaired spatial learning. However, we demonstrated that PATs inhibition during the retrieval does not affect the expression of spatial memory in both MWM and OLM. Accordingly, long-term potentiation induction is impaired by inhibiting PATs into the hippocampus before high-frequency electrical stimulation but not after. These findings suggest that PATs activity is necessary to modify neural plasticity, a mechanism required for memory acquisition and consolidation. Like phosphorylation, active palmitoylation is required to regulate the function of already existing proteins that change synaptic strength in the hippocampus to acquire and later consolidate spatial memories.

Spatial contextual recognition memory updating is modulated by dopamine release in the dorsal hippocampus from the locus coeruleus.

Detecting novelty is critical to consolidate declarative memories, such as spatial contextual recognition memory. It has been shown that stored memories, when retrieved, are susceptible to modification, incorporating new information through an updating process. Catecholamine release in the hippocampal CA1 region consolidates an object location memory (OLM). This work hypothesized that spatial contextual memory updating could be changed by decreasing catecholamine release in the hippocampal CA1 terminals from the locus coeruleus (LC). In a mouse model expressing Cre-recombinase under the control of the tyrosine hydroxylase (TH) promoter, memory updating was impaired by photoinhibition of the CA1 catecholaminergic terminals from the LC (LC-CA1) but not from the ventral tegmental area (VTA-CA1). In vivo microdialysis confirmed that the extracellular concentration of both dopamine (DA) and noradrenaline (NA) decreased after photoinhibition of the LC-CA1 terminals (but not VTA-CA1) during the OLM update session. Furthermore, DA D1/D5 and beta-adrenergic receptor antagonists disrupted behavior, but only the former impaired memory updating. Finally, photoinhibition of LC-CA1 terminals suppressed long-term potentiation (LTP) induction in Schaffer's collaterals as a plausible mechanism for memory updating. These data will help understand the underpinning mechanisms of DA in spatial contextual memory updating.

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.

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.

Photostimulation of Ventral Tegmental Area-Insular Cortex Dopaminergic Inputs Enhances the Salience to Consolidate Aversive Taste Recognition Memory via D1-Like Receptors.

Taste memory involves storing information through plasticity changes in the neural network of taste, including the insular cortex (IC) and ventral tegmental area (VTA), a critical provider of dopamine. Although a VTA-IC dopaminergic pathway has been demonstrated, its role to consolidate taste recognition memory remains poorly understood. We found that photostimulation of dopaminergic neurons in the VTA or VTA-IC dopaminergic terminals of TH-Cre mice improves the salience to consolidate a subthreshold novel taste stimulus regardless of its hedonic value, without altering their taste palatability. Importantly, the inhibition of the D1-like receptor into the IC impairs the salience to facilitate consolidation of an aversive taste recognition memory. Finally, our results showed that VTA photostimulation improves the salience to consolidate a conditioned taste aversion memory through the D1-like receptor into the IC. It is concluded that the dopamine activity from the VTA into IC is required to increase the salience enabling the consolidation of a taste recognition memory. Notably, the D1-like receptor activity into the IC is required to consolidate both innate and learned aversive taste memories but not appetitive taste memory.

Maintenance of conditioned place avoidance induced by gastric malaise requires NMDA activity within the ventral hippocampus.

It has been reported that during chemotherapy treatment, some patients can experience nausea before pharmacological administration, suggesting that contextual stimuli are associated with the nauseating effects. There are attempts to reproduce with animal models the conditions under which this phenomenon is observed to provide a useful paradigm for studying contextual aversion learning and the brain structures involved. This manuscript assessed the hippocampus involvement in acquiring and maintaining long-term conditioned place avoidance (CPA) induced by a gastric malaise-inducing agent, LiCl. Our results demonstrate that a reliable induction of CPA is possible after one acquisition trial. However, CPA establishment requires a 20-min confinement in the compartment associated with LiCl administration. Interestingly, both hippocampal regions seem to be necessary for CPA establishment; nonetheless, inactivation of the ventral hippocampus results in a reversion of avoidance and turns it into preference. Moreover, we demonstrate that activation of dorsal/ventral hippocampal NMDA receptors after CS-US association is required for long-term CPA memory maintenance.

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.

Class I HDAC inhibition improves object recognition memory consolidation through BDNF/TrkB pathway in a time-dependent manner.

There is increasing evidence showing that HDACs regulates BDNF (brain-derived neurotrophic factor) expression through its interaction with the Bdnf gene promoter, a key regulator to consolidate memory. Although the nuclear mechanisms regulated by HDACs that control BDNF expression have been partially described recently, the temporal events for memory consolidation remain unknown. Hence, in this work, we studied the temporal pattern for the activation of the BDNF/TrkB pathway through class I HDAC inhibition to enhance object recognition memory (ORM) consolidation. To this end, we inhibited class I HDAC into the insular cortex (IC) and a weak ORM protocol was used to assess temporal expression and function of the BDNF/TrkB pathway in the IC. We found that cortical class I HDAC inhibition enhanced long-term ORM, coincident with a clear peak of BDNF expression at 4 h after acquisition. Furthermore, the tyrosine kinase B (TrkB) receptor blockade at 4 h, but not at 8 h, impaired the consolidation of ORM. These results suggest that histone acetylation regulates the temporal expression of BDNF in cortical circuits potentiating the long-term recognition memory.

Age-Dependent Decline in Synaptic Mitochondrial Function Is Exacerbated in Vulnerable Brain Regions of Female 3xTg-AD Mice.

Synaptic aging has been associated with neuronal circuit dysfunction and cognitive decline. Reduced mitochondrial function may be an early event that compromises synaptic integrity and neurotransmission in vulnerable brain regions during physiological and pathological aging. Thus, we aimed to measure mitochondrial function in synapses from three brain regions at two different ages in the 3xTg-AD mouse model and in wild mice. We found that aging is the main factor associated with the decline in synaptic mitochondrial function, particularly in synapses isolated from the cerebellum. Accumulation of toxic compounds, such as tau and Aß, that occurred in the 3xTg-AD mouse model seemed to participate in the worsening of this decline in the hippocampus. The changes in synaptic bioenergetics were also associated with increased activation of the mitochondrial fission protein Drp1. These results suggest the presence of altered mechanisms of synaptic mitochondrial dynamics and their quality control during aging and in the 3xTg-AD mouse model; they also point to bioenergetic restoration as a useful therapeutic strategy to preserve synaptic function during aging and at the early stages of Alzheimer's disease (AD).

Telomere length and oxidative stress variations in a murine model of Alzheimer's disease progression.

Alzheimer's disease (AD) is the most common cause of dementia, and ageing is its major risk factor. Changes in telomere length have been associated with ageing and some degenerative diseases. Our aim was to explore some of the molecular changes caused by the progression of AD in a transgenic murine model (3xTg-AD; B6; 129-Psen1 Tg (APPSwe, tauP301L) 1Lfa). Telomere length was assessed by qPCR in both brain tissue and peripheral blood cells and compared between three age groups: 5, 9 and 13 months. In addition, a possible effect of oxidative stress on telomere length and AD progression was explored. Shorter telomeres were found in blood cells of older transgenic mice compared to younger and wild-type mice but no changes in telomere length in the hippocampus. An increase in oxidative stress with age was found for all strains, but no correlation was found between oxidative stress and shorter telomere length for transgenic mice. Telomere length and oxidative stress are affected by AD progression in the 3xTg-AD murine model. Changes in blood cells are more noticeable than changes in brain tissue, suggesting that systemic changes can be detected early in the disease in this murine model.

Glutamatergic basolateral amygdala to anterior insular cortex circuitry maintains rewarding contextual memory.

Findings have shown that anterior insular cortex (aIC) lesions disrupt the maintenance of drug addiction, while imaging studies suggest that connections between amygdala and aIC participate in drug-seeking. However, the role of the BLA â†’ aIC pathway in rewarding contextual memory has not been assessed. Using a cre-recombinase under the tyrosine hydroxylase (TH+) promoter mouse model to induce a real-time conditioned place preference (rtCPP), we show that photoactivation of TH+ neurons induced electrophysiological responses in VTA neurons, dopamine release and neuronal modulation in the aIC. Conversely, memory retrieval induced a strong release of glutamate, dopamine, and norepinephrine in the aIC. Only intra-aIC blockade of the glutamatergic N-methyl-D-aspartate receptor accelerated rtCPP extinction. Finally, photoinhibition of glutamatergic BLA → aIC pathway produced disinhibition of local circuits in the aIC, accelerating rtCPP extinction and impairing reinstatement. Thus, activity of the glutamatergic projection from the BLA to the aIC is critical for maintenance of rewarding contextual memory.