Carlos J. Rodriguez-Ortiz

The consolidation of object and context recognition memory involve different regions of the temporal lobe

These experiments investigated the involvement of several temporal lobe regions in consolidation of recognition memory. Anisomycin, a protein synthesis inhibitor, was infused into the hippocampus, perirhinal cortex, insular cortex, or basolateral amygdala of rats immediately after the sample phase of object or object-in-context recognition memory training. Anisomycin infused into perirhinal or insular cortices blocked long-term (24 h), but not short-term (90 min) object recognition memory. Infusions into the hippocampus or amygdala did not impair object recognition memory. Anisomycin infused into the hippocampus blocked long-term, but not short-term object-in-context recognition memory, whereas infusions administered into the perirhinal cortex, insular cortex, or amygdala did not affect object-in-context recognition memory. These results clearly indicate that distinct regions of the temporal lobe are differentially involved in long-term object and object-in-context recognition memory. Whereas perirhinal and insular cortices are required for consolidation of familiar objects, the hippocampus is necessary for consolidation of contextual information of recognition memory. Altogether, these results suggest that temporal lobe structures are differentially involved in recognition memory consolidation.

Intrahippocampal anisomycin infusions disrupt previously consolidated spatial memory only when memory is updated.

Reconsolidation has proven to be a common phenomenon relevant to memory processing. However, the functional significance of this process is still a matter of debate. Previous work has shown that reconsolidation is indeed a process by which updated information is integrated, through the synthesis of proteins, to a memory trace. To further analyze the role that updated information plays in retrieved spatial memory susceptibility to disruption, we injected anisomycin bilaterally in the dorsal hippocampus of Wistar rats. Implanted animals were trained for 5 days on the Morris water maze (MWM) task and injected with anisomycin before the third or fifth training session. When memory was assessed a week later, only animals injected on the third training session showed disruption of long-term memory. Furthermore, when animals were trained for either 3 (middle-trained) or 5 (well-trained) days and a week later anisomycin was infused before a reminder session, only middle-trained rats infused with anisomycin showed reduced performance when tested for long-term memory. Finally, animals trained for 5 days and injected with anisomycin 7 days later on an extinction session showed impaired long-term extinction when tested. These results suggest that for spatial memory tasks acquisition of updated information is a necessary feature to undergo this process. We propose that reconsolidation is not an accurate term because it implies that consolidation happens again. This conception does not fit with the evidence; hence, we suggest that updating consolidation is a more descriptive term to refer to this process.

Cholinergic dependence of taste memory formation: Evidence of two distinct processes

Learning the aversive or positive consequences associated with novel taste solutions has a strong significance for an animals survival. A lack of recognition of a tastes consequences could prevent ingestion of potential edibles or encounter death. We used conditioned taste aversion (CTA) and attenuation of neophobia (AN) to study aversive and safe taste memory formation. To determine if muscarinic receptors in the insular cortex participate differentially in both tasks, we infused the muscarinic antagonists scopolamine at distinct times before or after the presentation of a strong concentration of saccharin, followed by either an i.p. injection of a malaise-inducing agent or no injection. Our results showed that blockade of muscarinic receptors before taste presentation disrupts both learning tasks. However, the same treatment after the taste prevents AN but not CTA. These results clearly demonstrate that cortical cholinergic activity participates in the acquisition of both safe and aversive memory formation, and that cortical muscarinic receptors seem to be necessary for safe but not for aversive taste memory consolidation. These results suggest that the taste memory trace is processed in the insular cortex simultaneously by at least two independent mechanisms, and that their interaction would determine the degree of aversion or preference learned to a novel taste.

Basolateral amygdala glutamatergic activation enhances taste aversion through NMDA receptor activation in the insular cortex

In conditioned taste aversion (CTA), a subject learns to associate a novel taste with visceral malaise. Brainstem, limbic and neocortical structures have been implicated in CTA memory formation. Nevertheless, the role of interactions between forebrain structures during these processes is still unknown. The present experiment was aimed at investigating the possible interaction between the basolateral nucleus of the amygdala (BLA) and the insular cortex (IC) during CTA memory formation. Injection of a low dose of lithium chloride (30 mg/kg, i.p.) 30 min after novel taste consumption (saccharin 0.1%) induces a weak CTA. Unilateral BLA injection of glutamate (2 µg in 0.5 µL) just before low lithium induces a stronger CTA. Unilateral injection of an N‐methyl‐d‐aspartate (NMDA) receptor antagonist (AP5, 5 µg in 0.5 µL) in IC has no effect. However, AP5 treatment in IC at the same time or 1 h after the ipsilateral BLA injection reverses the glutamate‐induced CTA enhancement. Injection of AP5 in IC 3 h after BLA injection does not interfere with the glutamate effect. Moreover, the CTA‐enhancing effect of glutamate was also blocked by contralateral IC injection of AP5 at the same time. These results provide strong evidence that NMDA receptor activation in the IC is essential to enable CTA enhancement induced by glutamate infusion in the BLA during a limited time period that extends to 1 but not to 3 hours. These findings indicate that BLA–IC interactions regulate the strength of CTA. The bilateral nature of these amygdalo–cortical interactions is discussed.

Ceftriaxone ameliorates tau pathology and cognitive decline via restoration of glial glutamate transporter in a mouse model of Alzheimer's disease.

Glial glutamate transporter, GLT-1, is the major Na(+)-driven glutamate transporter to control glutamate levels in synapses and prevent glutamate-induced excitotoxicity implicated in neurodegenerative disorders including Alzheimers disease (AD). Significant functional loss of GLT-1 has been reported to correlate well with synaptic degeneration and severity of cognitive impairment among AD patients, yet the underlying molecular mechanism and its pathological consequence in AD are not well understood. Here, we find the temporal decrease in GLT-1 levels in the hippocampus of the 3xTg-AD mouse model and that the pharmacological upregulation of GLT-1 significantly ameliorates the age-dependent pathological tau accumulation, restores synaptic proteins, and rescues cognitive decline with minimal effects on Aβ pathology. In primary neuron and astrocyte coculture, naturally secreted Aβ species significantly downregulate GLT-1 steady-state and expression levels. Taken together, our data strongly suggest that GLT-1 restoration is neuroprotective and Aβ-induced astrocyte dysfunction represented by a functional loss of GLT-1 may serve as one of the major pathological links between Aβ and tau pathology.

Short‐term modern life‐like stress exacerbates Aβ‐pathology and synapse loss in 3xTg‐AD mice

Alzheimers disease (AD) is a progressive neurological disorder that impairs memory and other cognitive functions in the elderly. The social and financial impacts of AD are overwhelming and are escalating exponentially as a result of population aging. Therefore, identifying AD‐related risk factors and the development of more efficacious therapeutic approaches are critical to cure this neurological disorder. Current epidemiological evidence indicates that life experiences, including chronic stress, are a risk for AD. However, it is unknown if short‐term stress, lasting for hours, influences the onset or progression of AD. Here, we determined the effect of short‐term, multi‐modal ‘modern life‐like’ stress on AD pathogenesis and synaptic plasticity in mice bearing three AD mutations (the 3xTg‐AD mouse model). We found that combined emotional and physical stress lasting 5 h severely impaired memory in wild‐type mice and tended to impact it in already low‐performing 3xTg‐AD mice. This stress reduced the number of synapse‐bearing dendritic spines in 3xTg‐AD mice and increased Aβ levels by augmenting AβPP processing. Thus, short‐term stress simulating modern‐life conditions may exacerbate cognitive deficits in preclinical AD by accelerating amyloid pathology and reducing synapse numbers.

Simultaneous but not independent anisomycin infusions in insular cortex and amygdala hinder stabilization of taste memory when updated

Reconsolidation has been described as a process where a consolidated memory returns to a labile state when retrieved. Growing evidence suggests that reconsolidation is, in fact, a destabilization/stabilization process that incorporates updated information to a previously consolidated memory. We used the conditioned taste aversion (CTA) task in order to test this theory. On the first trial, the conditioned stimulus (CS) (saccharin) was associated to the unconditioned stimulus (US) (LiCl injection), and as a result, aversion to saccharin was obtained. The following day, animals were injected with anisomycin in either the insular cortex (IC), central amygdala (CeA), basolateral amygdala (BLA), or simultaneously in IC and CeA or IC and BLA, and a second CTA trial was carried out in which updated information was acquired. Animals were tested 24 h later. When protein synthesis was inhibited in either the IC or CeA, consolidation was affected and previously consolidated memory was unimpaired. However, when both the IC and CeA were simultaneously anisomycin injected, the previously consolidated memory was affected. After repeated association trials, protein synthesis inhibition in the IC and CeA did not have an effect on taste memory. These results suggest that the IC and the CeA are necessary for taste-aversion consolidation, and that both share the previously consolidated memory trace. In addition, our data demonstrated that protein synthesis in either the IC or the CeA suffices to stabilize previously consolidated taste memory when destabilized by incorporation of updated information.

Taste aversion memory reconsolidation is independent of its retrieval.

Reconsolidation refers to the destabilization/re-stabilization memory process upon its activation. However, the conditions needed to undergo reconsolidation, as well as its functional significance is quite unclear and a matter of intense investigation. Even so, memory retrieval is held as requisite to initiate reconsolidation. Therefore, in the present work we examined whether transient pharmacological disruption of memory retrieval impedes reconsolidation of stored memory in the widely used associative conditioning task, taste aversion. We found that AMPA receptors inhibition in the amygdala impaired retrieval of taste aversion memory. Furthermore, AMPA receptors blockade impeded retrieval regardless of memory strength. However, inhibition of retrieval did not affect anisomycin-mediated disruption of reconsolidation. These results indicate that retrieval is a dispensable condition to undergo reconsolidation and provide evidence of molecular dissociation between retrieval and activation of memory in the non-declarative memory model taste aversion.

Infection, systemic inflammation, and Alzheimer's disease

Alzheimers disease (AD) is a leading cause of dementia among elderly. Yet, its etiology remains largely unclear. In this review, we summarize studies that associate systemic infection and neuroinflammation with AD, while highlighting that early-life or life-long exposure to infectious agents predisposes one to develop AD at a later age.

Medial temporal lobe structures participate differentially in consolidation of safe and aversive taste memories

Taste memories are amongst the most important kinds of memories, as adequate identification of safe and toxic edibles will determine the subject’s survival. Despite the well‐established role that the medial temporal lobe plays in consolidation of memory, specific contributions of the different regions of the temporal lobe to taste memory consolidation remain unknown. In the present report, we assessed the participation of perirhinal cortex (Ph), dorsal hippocampus (Hipp), basolateral (BLA) and central nuclei of the amygdala (CeA) in safe and aversive taste memories by means of local infusions of the protein synthesis inhibitor anisomycin in the rat. The results showed that protein synthesis in the CeA, but not BLA, is required to stabilize taste aversion memory. Surprisingly, the Ph and Hipp seem to be essential to consolidate safe taste memory. These data suggest that different networks within the temporal lobe are recruited to consolidate memory depending on the consequences associated with tastes.