Biology subjects

Leake, J.

Publications and source records attributed to Leake, J..

4 recordsLinked to original sources

bioRxiv2022

What is learned determines how Pavlovian conditioned fear is consolidated in the brain.

Activity in the basolateral amygdala complex (BLA) is needed to encode fears acquired through contact with both innate sources of danger (i.e., things that are painful) and learned sources of danger (e.g., being threatened with a gun). However, within the BLA, the molecular processes required to consolidate the two types of fear are not the same: protein synthesis is needed to consolidate the first type of fear (so-called first-order fear) but not the latter (so-called second-order fear). The present study examined why first- and second-order fears differ in this respect. To do so, it used a range of conditioning protocols in rats and assessed the effects of a BLA infusion of the protein synthesis inhibitor, cycloheximide, on fear to first- and second-order conditioned stimuli. The results revealed that the differential protein synthesis requirements for consolidation of first- and second-order fears reflect differences in what is learned in each case. Protein synthesis in the BLA is needed to consolidate fears that result from encoding of relations between stimuli in the environment (stimulus-stimulus associations, typical for first-order fear) but is not needed to consolidate fears that form when environmental stimuli associate directly with fear responses emitted by the animal (stimulus-response associations, typical for second-order fear). Thus, the substrates of Pavlovian fear conditioning in the BLA depend on the way that the environment impinges upon the animal. This is discussed with respect to theories of amygdala function in Pavlovian fear conditioning, and ways in which stimulus-response associations might be consolidated in the brain.

animal behavior and cognition↗

bioRxiv2022

Danger changes the way the brain consolidates neutral information; and does so by interacting with processes involved in the encoding of that information.

This study examined the effect of danger on consolidation of neutral information in two regions of the rat (male and female) medial temporal lobe: the perirhinal cortex (PRh) and basolateral amygdala complex (BLA). The neutral information was the association that forms between an auditory stimulus and a visual stimulus (labelled S2 and S1) across their pairings in sensory preconditioning. We show that, when the sensory preconditioning session is followed by a shocked context exposure, the danger shifts consolidation of the S2-S1 association from the PRh to the BLA; and does so by interacting with processes involved in encoding of the S2-S1 pairings. Specifically, we show that the initial S2-S1 pairing in sensory preconditioning is encoded in the BLA and not the PRh; whereas the later S2-S1 pairings are encoded in the PRh and not the BLA. When the sensory preconditioning session is followed by a context alone exposure, the BLA-dependent trace of the early S2-S1 pairings decays and the PRh-dependent trace of the later S2-S1 pairings is consolidated in memory. However, when the sensory preconditioning session is followed by a shocked context exposure, the PRh-dependent trace of the later S2-S1 pairings is suppressed and the BLA-dependent trace of the initial S2-S1 pairing is consolidated in memory. These findings are discussed with respect to mutually inhibitory interactions between the PRh and BLA, and the way that these regions support memory in other protocols, including recognition memory in people. Significance StatementThe perirhinal cortex (PRh) and basolateral amygdala complex (BLA) process the pairings of neutral auditory and visual stimuli in sensory preconditioning. The involvement of each region in this processing is determined by the novelty/familiarity of the stimuli as well as events that occur immediately after the preconditioning session. Novel stimuli are represented in the BLA; however, as these stimuli are repeatedly presented without consequence, they come to be represented in the PRh. Whether the BLA- or PRh-dependent representation is consolidated in memory depends on what happens next. When nothing of significance occurs, the PRh-dependent representation is consolidated and the BLA-dependent representation decays; but when danger is encountered, the PRh-dependent representation is inhibited and the BLA-dependent representation is selected for consolidation.

animal behavior and cognition↗

bioRxiv2022

Contextual and temporal regulation of fear memory consolidation in the basolateral amygdala complex

It is widely accepted that fear memories are consolidated through protein synthesis-dependent changes in the basolateral amygdala complex (BLA). However, recent studies show that protein synthesis is not required to consolidate the memory of a new dangerous experience when it is similar to a prior experience. Here, we examined whether the protein synthesis requirement for consolidation of the new experience varies with its spatial and temporal distance from the prior experience. In each experiment, rats were conditioned to fear a stimulus (S1, e.g., light) across its pairings with shock in stage 1; and a second stimulus (S2, e.g., tone) that preceded additional S1-shock pairings (S2-S1-shock) in stage 2. The latter stage was followed by a BLA infusion of a protein synthesis inhibitor, cycloheximide or vehicle. Finally, rats were tested for fear to S2. Critically, protein synthesis in the BLA was not required to consolidate fear to S2 when the two training stages occurred 48 hours apart and in the same context; was required when the two training stages were separated by a 14-day delay or occurred in different contexts; but was again not required when rats were re-exposed to S1 or shock after the delay or in the different context. Thus, protein synthesis in the BLA is not always required to consolidate a new fear memory. Instead, this requirement is determined by the degree of similarity between present and past experiences, the time and place in which those experiences occur, as well as reminders of the past experience. Significance StatementProtein synthesis in the basolateral amygdala complex (BLA) is not required to consolidate the memory of a new dangerous experience when it is similar to a prior experience. This study is significant in showing that: 1) when the new, similar experience occurs after a delay or in a different context, the protein synthesis requirement for its consolidation is reinstated; and 2) the effects of the delay and context shift are reversed by reminding animals of their prior experience. Thus, the neural mechanisms underlying memory consolidation are dynamically regulated by similarity/dissimilarity between present and past experiences, the time and place in which those experiences occur, as well as reminders of the past experience.

animal behavior and cognition↗

bioRxiv2022

Goal-directed action is transiently impaired in an hAPP-J20 mouse model of Alzheimer's disease, and in aging male mice regardless of genotype

Cognitive-behavioural testing in preclinical models of Alzheimers disease has typically been limited to visuo-spatial memory tests and has failed to capture the broad scope of deficits patients also display in goal-directed action control. The current study addresses this gap by providing the first comprehensive investigation of how goal-directed actions are affected in a transgenic mouse model of Alzheimers disease. Specifically, we tested outcome devaluation performance - a popular test of goal-directed action - in male and female human amyloid precursor protein (hAPP)-J20 mice. Mice were first trained to press a left and right lever for unique pellet and sucrose outcomes respectively (counterbalanced) over four days. On test, mice were fed one of the two outcomes to reduce its value via sensory specific satiety and subsequently given a choice between levers. Goal-directed action was intact for 36-week-old wildtype mice of both sexes, because they responded more on the lever associated with the still-valued outcome than that associated with the devalued outcome (i.e. Valued > Devalued). Goal-directed action was impaired (Valued = Devalued) for J20 mice of both sexes, and for 52-week-old male mice regardless of genotype. Following an additional 4 days of lever press training (i.e., 8 days lever pressing in total), outcome devaluation was intact for all mice regardless of age or genotype. Immunohistochemical analysis revealed that increased microglial expression in the dorsal CA1 region of the hippocampus was associated with poorer outcome devaluation performance on initial tests, but not with tests performed after 8 days of lever pressing. Together, these data demonstrate that goal-directed action is transiently impaired in J20 mice of both sexes and in aging male mice regardless of genotype, and that this impairment is related to neuroinflammation in the dorsal CA1 region of the hippocampus.

animal behavior and cognition↗