The role of the lateral orbitofrontal cortex in creating cognitive maps.

We use mental models of the world-cognitive maps-to guide behavior. The lateral orbitofrontal cortex (lOFC) is typically thought to support behavior by deploying these maps to simulate outcomes, but recent evidence suggests that it may instead support behavior by underlying map creation. We tested between these two alternatives using outcome-specific devaluation and a high-potency chemogenetic approach. Selectively inactivating lOFC principal neurons when male rats learned distinct cue-outcome associations, but before outcome devaluation, disrupted subsequent inference, confirming a role for the lOFC in creating new maps. However, lOFC inactivation surprisingly led to generalized devaluation, a result that is inconsistent with a complete mapping failure. Using a reinforcement learning framework, we show that this effect is best explained by a circumscribed deficit in credit assignment precision during map construction, suggesting that the lOFC has a selective role in defining the specificity of associations that comprise cognitive maps.

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.

'Arc'-hitecture of normal cognitive aging.

Arc is an effector immediate-early gene that is critical for forming long-term memories. Since its discovery 25 years ago, it has repeatedly surprised us with a number of intriguing properties, including the transport of its mRNA to recently-activated synapses, its master role in bidirectionally regulating synaptic strength, its evolutionary retroviral origins, its ability to mediate intercellular transfer between neurons via extracellular vesicles (EVs), and its exceptional regulation-both temporally and spatially. The current review discusses how Arc has been used as a tool to identify the neural networks involved in cognitive aging and how Arc itself may contribute to cognitive outcome in aging. In addition, we raise several outstanding questions, including whether Arc-containing EVs in peripheral blood might provide a noninvasive biomarker for memory-related synaptic failure in aging, and whether rectifying Arc dysregulation is likely to be an effective strategy for bending the arc of aging toward successful cognitive outcomes.

Improved post-stroke spontaneous recovery by astrocytic extracellular vesicles.

Spontaneous recovery after a stroke accounts for a significant part of the neurological recovery in patients. However limited, the spontaneous recovery is mechanistically driven by axonal restorative processes for which several molecular cues have been previously described. We report the acceleration of spontaneous recovery in a preclinical model of ischemia/reperfusion in rats via a single intracerebroventricular administration of extracellular vesicles released from primary cortical astrocytes. We used magnetic resonance imaging and confocal and multiphoton microscopy to correlate the structural remodeling of the corpus callosum and striatocortical circuits with neurological performance during 21 days. We also evaluated the functionality of the corpus callosum by repetitive recordings of compound action potentials to show that the recovery facilitated by astrocytic extracellular vesicles was both anatomical and functional. Our data provide compelling evidence that astrocytes can hasten the basal recovery that naturally occurs post-stroke through the release of cellular mediators contained in extracellular vesicles.

Effects of repetitive Transcranial Magnetic Stimulation in aged rats depend on pre-treatment cognitive status: Toward individualized intervention for successful cognitive aging.

BACKGROUND: Repetitive Transcranial Magnetic Stimulation (rTMS) has shown initial promise in combating age-related cognitive decline and dementia. The nature and severity of cognitive aging, however, varies markedly between individuals. OBJECTIVE/HYPOTHESIS: We hypothesized that the distinct constellation of brain changes responsible for individual differences in cognitive aging might influence the response to rTMS. METHODS: Cognitive effects of rTMS were evaluated using a rat model of cognitive aging in which aged rats are classified as Aged-Impaired (AI) or -Unimpaired (AU) relative to young (Y) according to their performance in the Morris water maze. Several weeks later, following presentation of a sample odor in an olfactory recognition task, rats received either sham (Y, n = 9; AU, n = 8; AI, n = 9) or intermittent Theta Burst Stimulation (Y, n = 8; AU, n = 8; AI, n = 9). Memory was tested 24 h later. RESULTS: Recognition memory in the sham and stimulated conditions depended on pre-treatment cognitive status in the aged rats. Y and AU sham rats displayed robust odor recognition, whereas sham-treated AI rats exhibited no retention. In contrast, rTMS treated AI rats showed robust retention, comparable in magnitude to Y, whereas the AU stimulated scored at chance. CONCLUSION: Our results are consistent with a perspective that the unique neurobiology associated with variability in cognitive aging modulates the response to rTMS. Protocols with documented efficacy in young adults may have unexpected outcomes in aging or neurodegenerative conditions, requiring individualized approaches.

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).

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.

Transcriptional, Behavioral and Biochemical Profiling in the 3xTg-AD Mouse Model Reveals a Specific Signature of Amyloid Deposition and Functional Decline in Alzheimer's Disease.

Alzheimer's disease (AD)-related degenerative decline is associated to the presence of amyloid beta (Aß) plaque lesions and neuro fibrillary tangles (NFT). However, the precise molecular mechanisms linking Aß deposition and neurological decline are still unclear. Here we combine genome-wide transcriptional profiling of the insular cortex of 3xTg-AD mice and control littermates from early through to late adulthood (2-14 months of age), with behavioral and biochemical profiling in the same animals to identify transcriptional determinants of functional decline specifically associated to build-up of Aß deposits. Differential expression analysis revealed differentially expressed genes (DEGs) in the cortex long before observed onset of behavioral symptoms in this model. Using behavioral and biochemical data derived from the same mice and samples, we found that down but not up-regulated DEGs show a stronger average association with learning performance than random background genes in control not seen in AD mice. Conversely, these same genes were found to have a stronger association with Aß deposition than background genes in AD but not in control mice, thereby identifying these genes as potential intermediaries between abnormal Aß/NFT deposition and functional decline. Using a complementary approach, gene ontology analysis revealed a highly significant enrichment of learning and memory, associative, memory, and cognitive functions only among down-regulated, but not up-regulated, DEGs. Our results demonstrate wider transcriptional changes triggered by the abnormal deposition of Aß/NFT occurring well before behavioral decline and identify a distinct set of genes specifically associated to abnormal Aß protein deposition and cognitive decline.

Hippocampal release of dopamine and norepinephrine encodes novel contextual information.

The detection and processing of novel information encountered in our environment is crucial for proper adaptive behavior and learning. Hippocampus is a prime structure for novelty detection that receives high-level inputs including context information. It is of our interest to understand the mechanisms by which the hippocampus processes contextual information. For this, we performed in vivo microdyalisis in order to monitor extracellular changes in neurotransmitter levels during Object Location Memory (OLM), a behavioral protocol developed to evaluate contextual information processing in recognition memory. Neurotransmitter release was evaluated in the dorsal hippocampus and insular cortex during OLM in 3-month-old B6129SF2/J mice. We found a simultaneous release of dopamine and norepinephrine in hippocampus during OLM, while neurochemical activity remained unaltered in the cortex. Additionally, we administered 6-hydroxy-dopamine (6-OHDA), a neurotoxic compound selective to dopaminergic and noradrenergic neurons, in the dorsal hippocampus in a different group of mice. Depletion of catecholaminergic terminals in the hippocampus by 6-OHDA impaired OLM but did not affect novel object recognition. Our results support the relevance of hippocampal catecholaminergic neurotransmission in recognition memory. The significance of catecholaminergic function may be extended to the clinical field as it has been reported that innervation of hippocampus by the noradrenergic and dopaminergic system is reduced and atrophied in aging and Alzheimer's disease brain. © 2017 Wiley Periodicals, Inc.

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.

Dopamine D1 receptor activity modulates object recognition memory consolidation in the perirhinal cortex but not in the hippocampus.

It has been proposed that distributed neuronal networks in the medial temporal lobe process different characteristics of a recognition event; the hippocampus has been associated with contextual recollection while the perirhinal cortex has been linked with familiarity. Here we show that D1 dopamine receptor activity in these two structures participates differentially in object recognition memory consolidation. The D1 receptor antagonist SCH23390 was infused bilaterally 15 min before a 5 min sample phase in either rats' perirhinal cortex or dorsal hippocampus, and they were tested 90 min for short-term memory or 24 h later for long-term memory. SCH23390 impaired long-term memory when infused in the perirhinal cortex but not when infused in the hippocampus. Conversely, when the D1 receptor agonist SKF38393 was infused 10 min before a 3 min sample phase in the perirhinal cortex, long-term memory was enhanced, however, this was not observed when the D1 agonist was infused in the hippocampus. Short-term memory was spared when SCH23390 or SKF38393 were infused in the perirhinal cortex or the dorsal hippocampus suggesting that acquisition was unaffected. These results suggest that dopaminergic transmission in these medial temporal lobe structures have a differential involvement in object recognition memory consolidation.

Restoration of dopamine release deficits during object recognition memory acquisition attenuates cognitive impairment in a triple transgenic mice model of Alzheimer's disease.

Previous findings indicate that the acquisition and consolidation of recognition memory involves dopaminergic activity. Although dopamine deregulation has been observed in Alzheimer's disease (AD) patients, the dysfunction of this neurotransmitter has not been investigated in animal models of AD. The aim of this study was to assess, by in vivo microdialysis, cortical and hippocampal dopamine, norepinephrine, and glutamate release during the acquisition of object recognition memory (ORM) in 5- and 10-mo-old triple-transgenic Alzheimer's disease mice (3xTg-AD) and to relate the extracellular changes to 24-h memory performance. Five- and 10-mo-old wild-type mice and 5-mo-old 3xTg-AD showed significant cortical but not hippocampal dopamine increase during object exploration. On a 24-h ORM test, these three groups displayed significant ORM. In contrast, 10-mo-old 3xTg-AD mice showed impaired dopamine release in the insular cortex during ORM acquisition, as well as significant impairment in ORM. In addition, cortical administration of a dopamine reuptake blocker produced an increase of dopamine levels in the 10-mo-old 3xTg-AD mice and attenuated the memory impairment. These data suggest that activation of the dopaminergic system in the insular cortex is involved in object recognition memory, and that dysfunction of this system contributes to the age-related decline in cognitive functioning of the 3xTg-AD mice.

Post-acquisition release of glutamate and norepinephrine in the amygdala is involved in taste-aversion memory consolidation.

Amygdala activity mediates the acquisition and consolidation of emotional experiences; we have recently shown that post-acquisition reactivation of this structure is necessary for the long-term storage of conditioned taste aversion (CTA). However, the specific neurotransmitters involved in such reactivation are not known. The aim of the present study was to investigate extracellular changes of glutamate, norepinephrine, and dopamine within the rat amygdala using in vivo microdialysis during the acquisition and 1-h post-acquisition of CTA paradigm. Microdialysis monitoring showed a significant norepinephrine increase related to novel taste exposure and a glutamate increase after gastric malaise induction by i.p. LiCl administration. Interestingly, we found a spontaneous concomitant increase of glutamate and norepinephrine, but not dopamine, 45 min after conditioning, suggesting the presence of aversive learning-dependent post-acquisition signals in the amygdala. These signals seem to be involved in CTA consolidation process, since post-trial blockade of N-methyl-D-aspartate or ß-adrenergic receptors impaired long- but not short-term memory. These data suggest that CTA long-term storage involves post-acquisition release of glutamate and norepinephrine in the amygdala.

Off-line concomitant release of dopamine and glutamate involvement in taste memory consolidation.

It has been postulated that memory consolidation process requires post-learning molecular changes that will support long-term experiences. In the present study, we assessed with in vivo microdialysis and capillary electrophoresis whether such changes involve the release of neurotransmitters at post-acquisition stages. Using conditioned taste aversion paradigm we observed spontaneous off-line (i.e. in absence of stimulation) dopamine and glutamate reactivation within the insular cortex about 45 min after the stimuli association. These increments did not appear in control groups that were unable to acquire the task, and it seems to be dependent on amygdala activity since its reversible inactivation by tetrodotoxin impaired cortical off-line release of both neurotransmitters and memory consolidation. In addition, blockade of dopaminergic D1 and/or NMDA receptors before the off-line activity impaired long- but not short-term memory. These results suggest that off-line extracellular increments of glutamate and dopamine have a significant functional role in consolidation of taste memory.