The role of uncertainty in regulating associative change.

Rescorla (2000, 2001) interpreted his compound test results to show that both common and individual error terms regulate associative change such that the element of a conditioned compound with the greater prediction error undergoes greater associative change than the one with the smaller prediction error. However, it has recently been suggested that uncertainty, not prediction error, is the primary determinant of associative change in people (Spicer et al., 2020, 2022). The current experiments use the compound test in a continuous outcome allergist task to assess the role of uncertainty in associative change, using two different manipulations of uncertainty: outcome uncertainty (where participants are uncertain of the level of the outcome on a particular trial) and causal uncertainty (where participants are uncertain of the contribution of the cue to the level of the outcome). We replicate Rescorla's compound test results in the case of both associative gains (Experiment 1) and associative losses (Experiment 3) and then provide evidence for greater change to more uncertain cues in the case of associative gains (Experiments 2 and 4), but not associative losses (Experiments 3 and 5). We discuss the findings in terms of the notion of theory protection advanced by Spicer et al., and other ways of thinking about the compound test procedure, such as that proposed by Holmes et al. (2019). (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Context and Time Regulate Fear Memory Consolidation and Reconsolidation 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 consolidating the new experience varies with its spatial and temporal distance from the prior experience. Female and male rats were conditioned to fear a stimulus (S1, e.g., light) paired 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. Subsequent testing with S2 revealed that protein synthesis in the BLA was not required to consolidate fear to S2 when the training stages occurred 48 h apart in the same context; was required when they were separated by 14 d or occurred in different contexts; but was again not required if S1 was re-presented after the delay or in the different context. Similarly, protein synthesis in the BLA was not required to reconsolidate fear to S2 when the training stages occurred 48 h apart but was required when they occurred 14 d apart. Thus, the protein synthesis requirement for consolidating/reconsolidating fear memories in the BLA is determined by similarity between present and past experiences, the time and place in which they occur, and reminders of the past experiences.

Stimulating oxytocin receptors in the basolateral amygdala enhances stimulus processing: Differential and consistent effects for stimuli paired with fear versus sucrose in extinction and reversal learning.

Oxytocin (OT) influences a range of social behaviors by enhancing the salience of social cues and regulating the expression of specific social behaviors (e.g., maternal care versus defensive aggression). We previously showed that stimulating OT receptors in the basolateral amygdala of rats also enhanced the salience of fear conditioned stimuli: relative to rats given vehicle infusions, rats infused with [Thr4,Gly7]-oxytocin (TGOT), a selective OT receptor agonist, showed greater discrimination between a cue predictive of danger, and one that signaled safety. In the present series of experiments using male rats, the effects of OT receptor activation in the basolateral amygdala on stimulus processing were examined further using conditioning protocols that consist of changes in stimulus-outcome contingencies (i.e., extinction and reversal), and with stimuli paired with aversive (i.e., foot shock) and appetitive (i.e., sucrose) outcomes. It was revealed that the effects of OTR stimulation diverge for aversive and appetitive learning - enhancing the former but not the latter. However, across both types of learning, OTR stimulation enhanced the detection of conditioned stimuli. Overall, these results are consistent with an emerging view of OT's effects on stimulus salience; facilitating the detection of meaningful stimuli while reducing responding to those that are irrelevant.

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. Specifically, it used a range of conditioning protocols in male and female rats, and assessed the effects of a BLA infusion of the protein synthesis inhibitor, cycloheximide, on first- and second-order conditioned fear. 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.

NMDA Receptors in the Basolateral Amygdala Complex Are Engaged for Pavlovian Fear Conditioning When an Animal's Predictions about Danger Are in Error.

It is widely accepted that Pavlovian fear conditioning requires activation of NMDA receptors (NMDARs) in the basolateral amygdala complex (BLA). However, it was recently shown that activation of NMDAR in the BLA is only required for fear conditioning when danger occurs unexpectedly; it is not required for fear conditioning when danger occurs as expected. This study tested the hypothesis that NMDARs in the BLA are engaged for Pavlovian fear conditioning when an animal's predictions regarding danger are in error. In each experiment, rats (females in Experiment 1 and males in Experiments 2-5) were conditioned to fear one stimulus, S1, when it was paired with foot-shock (S1→shock), and 48 h later, a second stimulus, S2, when it was presented in sequence with the already-conditioned S1 and foot-shock (S2→S1→shock). Conditioning to S2 occurred under a BLA infusion of the NMDAR antagonist, D-AP5 or vehicle. The subsequent tests of freezing to S2 alone and S1 alone revealed that the antagonist had no effect on conditioning to S2 when the shock occurred exactly as predicted by the S1, but disrupted this conditioning when the shock occurred earlier/later than predicted by S1, or at a stronger/weaker intensity. These results imply that errors in the timing or intensity of a predicted foot-shock engage NMDARs in the BLA for Pavlovian fear conditioning. They are discussed in relation to theories which propose a role for prediction error in determining how experiences are organized in memory and how activation of NMDAR in the BLA might contribute to this organization.SIGNIFICANCE STATEMENT This study is significant in showing that prediction error determines how a new experience is encoded with respect to a past experience and, thereby, whether NMDA receptors (NMDARs) in the basolateral amygdala complex (BLA) encode the new experience. When prediction error is small (e.g., danger occurs as and when expected), the new experience is encoded together with a past experience as part of the same "mental model," and NMDAR activation in the BLA is not needed for this encoding. By contrast, when prediction error is large (e.g., danger occurs at an unexpected intensity or time), the new experience is encoded separately from the past experience as part of a new mental model, and NMDAR activation in the BLA is needed for this encoding.

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 (labeled 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 STATEMENT The 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.

Second-order fear conditioning involves formation of competing stimulus-danger and stimulus-safety associations.

How do animals process experiences that provide contradictory information? The present study addressed this question using second-order fear conditioning in rats. In second-order conditioning, rats are conditioned to fear a stimulus, S1, through its pairings with foot-shock (stage 1); and some days later, a second stimulus, S2, through its pairings with the already-conditioned S1 (stage 2). However, as foot-shock is never presented during conditioning to S2, we hypothesized that S2 simultaneously encodes 2 contradictory associations: one that drives fear to S2 (S2-danger) and another that reflects the absence of the expected unconditioned stimulus and partially masks that fear (e.g. S2-safety). We tested this hypothesis by manipulating the substrates of danger and safety learning in the brain (using a chemogenetic approach) and assessing the consequences for second-order fear to S2. Critically, silencing activity in the basolateral amygdala (important for danger learning) reduced fear to S2, whereas silencing activity in the infralimbic cortex (important for safety learning) enhanced fear to S2. These bidirectional changes are consistent with our hypothesis that second-order fear conditioning involves the formation of competing S2-danger and S2-safety associations. More generally, they show that a single set of experiences can produce contradictory associations and that the brain resolves the contradiction by encoding these associations in distinct brain regions.

The Benefits of Switching to a Healthy Diet on Metabolic, Cognitive, and Gut Microbiome Parameters Are Preserved in Adult Rat Offspring of Mothers Fed a High-Fat, High-Sugar Diet.

SCOPE: Maternal obesity increases the risk of health complications in children, highlighting the need for effective interventions. A rat model of maternal obesity to examine whether a diet switch intervention could reverse the adverse effects of an unhealthy postweaning diet is used. METHODS AND RESULTS: Male and female offspring born to dams fed standard chow or a high-fat, high-sugar "cafeteria" (Caf) diet are weaned onto chow or Caf diets until 22 weeks of age, when Caf-fed groups are switched to chow for 5 weeks. Adiposity, gut microbiota composition, and place recognition memory are assessed before and after the switch. Body weight and adiposity fall in switched groups but remain significantly higher than chow-fed controls. Nonetheless, the diet switch improves a deficit in place recognition memory observed in Caf-fed groups, increases gut microbiota species richness, and alters ß diversity. Modeling indicate that adiposity most strongly predicts gut microbiota composition before and after the switch. CONCLUSION: Maternal obesity does not alter the effects of switching diet on metabolic, microbial, or cognitive measures. Thus, a healthy diet intervention lead to major shifts in body weight, adiposity, place recognition memory, and gut microbiota composition, with beneficial effects preserved in offspring born to obese dams.

The influence of maternal unhealthy diet on maturation of offspring gut microbiota in rat.

BACKGROUND: Despite well-known effects of diet on gut microbiota diversity, relatively little is known about how maternal diet quality shapes the longitudinal maturation of gut microbiota in offspring. To investigate, we fed female rats standard chow (Chow) or a western-style, high-choice cafeteria diet (Caf) prior to and during mating, gestation and lactation. At weaning (3 weeks), male and female offspring were either maintained on their mother's diet (ChowChow, CafCaf groups) or switched to the other diet (ChowCaf, CafChow). Fecal microbial composition was assessed in dams and longitudinally in offspring at 3, 7 and 14 weeks of age. RESULTS: The effect of maternal diet on maturation of offspring gut microbiota was assessed by α- and ß-diversities, Deseq2/LEfSe, and SourceTracker analyses. Weanling gut microbiota composition was characterised by reduced α- and ß-diversity profiles that clustered away from dams and older siblings. After weaning, offspring gut microbiota came to resemble an adult-like gut microbiota, with increased α-diversity and reduced dissimilarity of ß-diversity. Similarly, Deseq2/LEfSe analyses found fewer numbers of altered operational taxonomic units (OTUs) between groups from weaning to adulthood. SourceTracker analyses indicated a greater overall contribution of Caf mothers' microbial community (up to 20%) to that of their offspring than the contribution of Chow mothers (up to 8%). Groups maintained on the maternal diet (ChowChow, CafCaf), versus those switched to the other diet (ChowCaf, CafChow) post-weaning significantly differed from each other at 14 weeks (Permutational Multivariate Analysis of Variance), indicating interactive effects of maternal and post-weaning diet on offspring gut microbiota maturation. Nevertheless, this developmental trajectory was unaffected by sex and appeared consistent between ChowChow, CafCaf, ChowCaf and CafChow groups. CONCLUSIONS: Introducing solid food at weaning triggered the maturation of offspring gut microbiota to an adult-like profile in rats, in line with previous human studies. Postweaning Caf diet exposure had the largest impact on offspring gut microbiota, but this was modulated by maternal diet history. An unhealthy maternal Caf diet did not alter the developmental trajectory of offspring gut microbiota towards an adult-like profile, insofar as it did not prevent the age-associated increase in α-diversity and reduction in ß-diversity dissimilarity.

Affective Valence Regulates Associative Competition in Pavlovian Conditioning.

Evidence suggests that, in Pavlovian conditioning, associations form between conditioned stimuli and multiple components of the unconditioned stimulus (US). It is common, for example, to regard USs as composed of sensory and affective components, the latter being either appetitive (e.g., food or water) or aversive (e.g., shock or illness) and, therefore, to suppose different USs of the same affective class activate a common affective system. Furthermore, evidence is growing for the suggestion that, in competitive learning situations, competition between predictive stimuli is primarily for association with the affective system activated by the US. Thus, a conditioned stimulus (CS) previously paired with one US will block conditioning to another CS when both are presented together and paired with a different US of the same affective class, a phenomenon called transreinforcer blocking. Importantly, similar effects have been reported when steps are taken to turn the pretrained CS into a conditioned inhibitor, which activates the opposing affective state to the excitor that it inhibits. Thus, an appetitive inhibitor can block conditioning to a second CS when they are presented together and paired with foot shock. Here we show that the same is true of an aversive inhibitor. In two experiments conducted in rats, we found evidence that an aversive inhibitor blocked conditioning to a second CS when presented in a compound and paired with food. Such findings demonstrate that affective processes and their opponency organize appetitive-aversive interactions and establish the valences on which they are based, consistent with incentive theories of Pavlovian conditioning.

Prediction Error Determines Whether NMDA Receptors in the Basolateral Amygdala Complex Are Involved in Pavlovian Fear Conditioning.

It is widely accepted that activation of NMDA receptors (NMDAR) is necessary for the formation of fear memories in the basolateral amygdala complex (BLA). This acceptance is based on findings that blockade of NMDAR in the BLA disrupts Pavlovian fear conditioning in rodents when initially innocuous stimuli are paired with aversive and unexpected events (surprising foot shock). The present study challenges this acceptance by showing that the involvement of NMDAR in Pavlovian fear conditioning is determined by prediction errors in relation to aversive events. In the initial experiments, male rats received a BLA infusion of the NMDAR antagonist, D-AP5 and were then exposed to pairings of a novel target stimulus and foot shock. This infusion disrupted acquisition of fear to the target when the shock was surprising (experiments 1a, 1b, 2a, 2b, 3a, and 3b) but spared fear to the target when the shock was expected based on the context, time and other stimuli that were present (experiments 1a and 1b). Under the latter circumstances, fear to the target required activation of calcium-permeable AMPAR (CP-AMPA; experiments 4a, 4b, and 4c), which, using electrophysiology, were shown to regulate the activity of interneurons in the BLA (experiment 5). Thus, NMDAR activation is not required for fear conditioning when danger occurs as expected given the context, time and stimuli present, but is required for fear conditioning when danger occurs unexpectedly. These findings are related to current theories of NMDAR function and ways that prediction errors might influence the substrates of fear memory formation in the BLA.SIGNIFICANCE STATEMENT It is widely accepted that NMDA receptors (NMDAR) in the basolateral amygdala complex (BLA) are activated by pairings of a conditioned stimulus (CS) and an aversive unconditioned (US) stimulus, leading to the synaptic changes that underlie formation of a CS-US association. The present findings are significant in showing that this theory is incomplete. When the aversive US is unexpected, animals encode all features of the situation (context, time and stimuli present) as a new fear/threat memory, which is regulated by NMDAR in the BLA. However, when the US is expected based on the context, time and stimuli present, the new fear memory is assimilated into networks that represent those features, which occurs independently of NMDAR activation in the BLA.

Male Rat Offspring Are More Impacted by Maternal Obesity Induced by Cafeteria Diet than Females-Additive Effect of Postweaning Diet.

Maternal obesity increases the risk of health complications in offspring, but whether these effects are exacerbated by offspring exposure to unhealthy diets warrants further investigation. Female Sprague-Dawley rats were fed either standard chow (n = 15) or 'cafeteria' (Caf, n = 21) diets across pre-pregnancy, gestation, and lactation. Male and female offspring were weaned onto chow or Caf diet (2-3/sex/litter), forming four groups; behavioural and metabolic parameters were assessed. At weaning, offspring from Caf dams were smaller and lighter, but had more retroperitoneal (RP) fat, with a larger effect in males. Maternal Caf diet significantly increased relative expression of ACACA and Fasn in male and female weanling liver, but not CPT-1, SREBP and PGC1; PPARα was increased in males from Caf dams. Maternal obesity enhanced the impact of postweaning Caf exposure on adult body weight, RP fat, liver mass, and plasma leptin in males but not females. Offspring from Caf dams appeared to exhibit reduced anxiety-like behaviour on the elevated plus maze. Hepatic CPT-1 expression was reduced only in adult males from Caf fed dams. Post weaning Caf diet consumption did not alter liver gene expression in the adult offspring. Maternal obesity exacerbated the obesogenic phenotype produced by postweaning Caf diet in male, but not female offspring. Thus, the impact of maternal obesity on adiposity and liver gene expression appeared more marked in males. Our data underline the sex-specific detrimental effects of maternal obesity on offspring.

The Opioid Receptor Antagonist Naloxone Enhances First-Order Fear Conditioning, Second-Order Fear Conditioning and Sensory Preconditioning in Rats.

The opioid receptor antagonist naloxone enhances Pavlovian fear conditioning when rats are exposed to pairings of an initially neutral stimulus, such as a tone, and a painful foot shock unconditioned stimulus (US; so-called first-order fear conditioning; Pavlov, 1927). The present series of experiments examined whether naloxone has the same effect when conditioning occurs in the absence of US exposure. In Experiments 1a and 1b, rats were exposed to tone-shock pairings in stage 1 (one trial per day for 4 days) and then to pairings of an initially neutral light with the already conditioned tone in stage 2 (one trial per day for 4 days). Experiment 1a confirmed that this training results in second-order fear of the light; and Experiment 1b showed that naloxone enhances this conditioning: rats injected with naloxone in stage 2 froze more than vehicle-injected controls when tested with the light alone (drug-free). In Experiments 2a and 2b, rats were exposed to light-tone pairings in stage 1 (one trial per day for 4 days) and then to tone-shock pairings in stage 2 (one trial per day for 2 days). Experiment 2a confirmed that this training results in sensory preconditioned fear of the light; and Experiment 2b showed that naloxone enhances sensory preconditioning when injected prior to each of the light-tone pairings: rats injected with naloxone in stage 1 froze more than vehicle-injected controls when tested with the light alone (drug-free). These results were taken to mean that naloxone enhances fear conditioning independently of its effect on US processing; and more generally, that opioids regulate the error-correction mechanisms that underlie associative formation.

Tamoxifen offers long-term neuroprotection after hippocampal silent infarct in male rats.

Silent infarcts (SI) are a cerebral small vessel disease characterized by small subcortical infarcts. These occur in the absence of typical ischemia symptoms but are linked to cognitive decline and dementia. While there are no approved treatments for SI, recent results from our laboratory suggest that tamoxifen, a selective estrogen receptor modulator, is a viable candidate. In the present study, we induced SI in the dorsal hippocampal CA1 region of rats and assessed the effects of systemic administration of tamoxifen (5 mg/kg, twice) 21 days after injury on cognitive and pathophysiological measures, including cell loss, apoptosis, gliosis and estrogen receptors (ERs). We found that tamoxifen protected against the SI-induced cognitive dysfunction on the hippocampal-dependent, place recognition task, cell and ER loss, and increased apoptosis and gliosis in the CA1. Exploratory data analyses using a scatterplot matrix and principal component analysis indicated that SI-tamoxifen rats were indistinguishable from sham controls while they differed from SI rats, who were characterized by enhanced cell loss, apoptosis and gliosis, lower ERs, and recognition memory deficit. Supervised machine learning using support vector machine (SVM) determined predictors of progression from the early ischemic state to the dementia-like state. It showed that caspase-3 and ERα in the CA1 and exploration proportion were reliable and accurate predictors of this progression. Importantly, tamoxifen ameliorated SI-induced effects on all three of these variables, providing further evidence for its viability as a candidate treatment for SI and prevention of associated dementia.

Latent inhibition is facilitated when a target stimulus is preexposed in compound with a nontarget stimulus, but only when the two stimuli coterminate: A test of the Hall-Rodriguez theory.

The Hall-Rodriguez (Hall & Rodriguez, 2010) theory predicts that latent inhibition can be facilitated when a target stimulus is preexposed in compound with a second, nontarget stimulus: specifically, latent inhibition will be facilitated when the target coterminates with the second stimulus in preexposure, but facilitation will fail to occur when the two stimuli do not coterminate. The present study tested these predictions. In each experiment, rats were preexposed to a 30 s target stimulus alone or in compound with a second stimulus across its final 10 s, or they were preexposed to the context. All rats were then exposed to pairings of the target stimulus and foot shock, and finally, tested for freezing to the target. Experiment 1 demonstrated standard latent inhibition. Experiment 2 provided evidence that preexposure to a 30 s auditory target stimulus, in compound with a visual stimulus across its final 10 s, produced facilitated latent inhibition. Experiment 3 demonstrated that the latent inhibition was also facilitated when each 30 s presentation of a target visual stimulus was compounded with an auditory stimulus across its final 10 s. Experiment 4 showed that facilitation did not occur when each 30 s presentation of the target was compounded with a second stimulus across its initial 10 s, while Experiment 5 found that latent inhibition of the target was impaired when each of its 30 s presentations terminated in the onset of a second (10 s) stimulus. These findings are consistent with the predictions of the Hall-Rodriguez theory. They confirm that the facilitation of latent inhibition depends on coterminations of target and nontarget stimuli in preexposure and, more generally, that the impact of a second stimulus on latent inhibition to a target depends on their temporal relation in preexposure. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The selective estrogen receptor modulator tamoxifen protects against subtle cognitive decline and early markers of injury 24 h after hippocampal silent infarct in male Sprague-Dawley rats.

Silent infarcts (SI) are subcortical cerebral infarcts occurring in the absence of typical ischemia symptoms and are linked to cognitive decline and dementia development. There are no approved treatments for SI. One potential treatment is tamoxifen, a selective estrogen receptor modulator. It is critical to establish whether treatments effectively target the early consequences of SI to avoid progression to complete injury. We induced SI in the dorsal hippocampal CA1 of rats and assessed whether tamoxifen is protective 24 h later against cognitive deficits and injury responses including gliosis, apoptosis, inflammation and changes in estrogen receptors (ERs). SI led to subtle cognitive impairment on the object place task, an effect ameliorated by tamoxifen administration. SI did not lead to detectable hippocampal cell loss but increased apoptosis, astrogliosis, microgliosis and inflammation. Tamoxifen protected against the effects of SI on all measures except microgliosis. SI increased ERα and decreased ERß in the hippocampus, which were mitigated by tamoxifen. Exploratory data analyses using scatterplot matrices and principal component analysis indicated that SI rats given tamoxifen were indistinguishable from controls. Further, SI rats were significantly different from all other groups, an effect associated with low levels of ERα and increased apoptosis, gliosis, inflammation, ERß, and time spent with the unmoved object. The results demonstrate that tamoxifen is protective against the early cellular and cognitive consequences of hippocampal SI 24 h after injury. Tamoxifen mitigates apoptosis, gliosis, and inflammation and normalization of ER levels in the CA1, leading to improved cognitive outcomes after hippocampal SI.

Acquisition and extinction of second-order context conditioned fear: Role of the amygdala.

Second-order fear conditioning has been demonstrated in protocols using discrete and simple stimuli, and much is now known about its behavioral and neural characteristics. In contrast, the mechanisms of second-order conditioning to more complex stimuli, such as contexts, are unknown. To address this gap in our knowledge, we conducted a series of experiments to investigate the neural and behavioral characteristics of second-order context fear conditioning in rats. We found that rats acquire fear to a context in which a first-order conditioned stimulus is presented (Experiment 1); neuronal activity in the basolateral amygdala (BLA) is required for the acquisition (Experiment 2) and extinction (Experiment 3) of second-order context fear; second-order context fear can be reduced by extinction of its first-order conditioned stimulus associate (Experiment 4); and that second-order fear reduced in this way is restored when fear of the first-order conditioned stimulus spontaneously recovers or is reconditioned (Experiment 5). Thus, second-order context fear requires neuronal activity in the BLA, and once established, tracks the level of fear to its first-order conditioned stimulus-associate. These results are discussed with respect to the substrates of second-order fear conditioning in other protocols, and the role of the amygdala in different forms of conditioning.

The separate and combined effects of a dangerous context and an epinephrine injection on sensory preconditioning in rats.

Four experiments examined the effects of a dangerous context and a systemic epinephrine injection on sensory preconditioning in rats. In each experiment, rats were exposed to presentations of a tone and light in stage 1, light-shock pairings in stage 2, and test presentations of the tone alone and light alone in stage 3. Presentations of the tone and light in stage 1 occurred in either a safe or a previously shocked context, and/or under a systemic injection of epinephrine. Experiment 1 showed that a trace interval of 20 sec between presentations of the tone and light produced sensory preconditioning of the tone in a previously shocked context but not in a safe context, while experiment 2 provided evidence that this trace preconditioning was associative, due to the formation of a tone-light association. Experiment 3 showed that, in a safe context, exposure to the trace protocol under the influence of an epinephrine injection also produced sensory preconditioning of the tone, while experiment 4 provided evidence that a shocked context and an epinephrine injection have additive effects on trace preconditioning. These findings are discussed in relation to theories of trace conditioning. They suggest that the release of epinephrine by danger enhances attention and/or working memory processes, and thereby associative formation across a trace interval.

Hippocampal silent infarct leads to subtle cognitive decline that is associated with inflammation and gliosis at twenty-four hours after injury in a rat model.

Silent infarcts (SI) are subcortical cerebral infarcts that occur in the absence of clinical symptoms commonly associated with ischemia and are linked to dementia development. Little is known about the pathophysiology underlying the cognitive dysfunction associated with SI, and few studies have examined the early cellular responses and neurobiological underpinnings. We induced SI in adult male Sprague-Dawley rats using an infusion of endothelin-1 in the CA1 dorsal hippocampus. Twenty-four hours later, we assessed cognition using the hippocampal-dependent object place recognition task. We also examined whether the resulting cognitive effects were associated with common markers of ischemia, specifically cell and synapse loss, gliosis, and inflammation, using histology and immunohistochemistry. Hippocampal SI led to subtle cognitive impairment on the object place recognition task 24 -hs post-injury. This was characterized by a significant difference in exploration proportion relative to a pre-injury baseline and a positive association between time spent with both the moved and unmoved objects. SI did not result in any detectable cell or synaptophysin loss, but did increase apoptosis, gliosis and inflammation in the CA1. Principal component analysis indicated the main variables associated with hippocampal SI included increased time spent with the unmoved object, gliosis, apoptosis and inflammation as well as decreased exploration proportion and CA1 cells. Our data demonstrate that hippocampal SI can lead to cognitive dysfunction 24 -hs after injury. Further, this appears to be driven by early degenerative processes including apoptosis, gliosis and inflammation, suggesting that these may be targets for early interventions treating hippocampal SI and its cognitive consequences.

Treadmill exercise has minimal impact on obesogenic diet-related gut microbiome changes but alters adipose and hypothalamic gene expression in rats.

BACKGROUND: Exercise has been extensively utilised as an effective therapy for overweight- and obesity-associated changes that are linked to health complications. Several preclinical rodent studies have shown that treadmill exercise alongside an unhealthy diet improves metabolic health and microbiome composition. Furthermore, chronic exercise has been shown to alter hypothalamic and adipose tissue gene expression in diet-induced obesity. However, limited work has investigated whether treadmill exercise commenced following exposure to an obesogenic diet is sufficient to alter microbiome composition and metabolic health. METHODS: To address this gap in the literature, we fed rats a high-fat/high-sugar western-style cafeteria diet and assessed the effects of 4 weeks of treadmill exercise on adiposity, diet-induced gut dysbiosis, as well as hypothalamic and retroperitoneal white adipose tissue gene expression. Forty-eight male Sprague-Dawley rats were allocated to either regular chow or cafeteria diet and after 3 weeks half the rats on each diet were exposed to moderate treadmill exercise for 4 weeks while the remainder were exposed to a stationary treadmill. RESULTS: Microbial species diversity was uniquely reduced in exercising chow-fed rats, while microbiome composition was only changed by cafeteria diet. Despite limited effects of exercise on overall microbiome composition, exercise increased inferred microbial functions involved in metabolism, reduced fat mass, and altered adipose and hypothalamic gene expression. After controlling for diet and exercise, adipose Il6 expression and liver triglyceride concentrations were significantly associated with global microbiome composition. CONCLUSIONS: Moderate treadmill exercise induced subtle microbiome composition changes in chow-fed rats but did not overcome the microbiome changes induced by prolonged exposure to cafeteria diet. Predicted metabolic function of the gut microbiome was increased by exercise. The effects of exercise on the microbiome may be modulated by obesity severity. Future work should investigate whether exercise in combination with microbiome-modifying interventions can synergistically reduce diet- and obesity-associated comorbidities.