Nathan M. Holmes

How does the brain integrate experiences that are separated in time? The present study addressed this question using sensory preconditioning protocols in rats. In these protocols, rats integrate an A-B association (e.g., tone-light) formed in stage 1 with a B- shock association (e.g., light-shock) formed in stage 2 to generate fear responses (freezing) when tested with A alone in stage 3. Here we show that the mechanism of integration depends on the number, order and timing of events across the two stages of training. When the events are novel (low number of exposures) and the interval between stages 1 and 2 is short (24 hours), the A-B and B-shock associations are integrated through formation of a mediated A- shock association during stage 2. By contrast, when the events are more familiar (greater number of exposures), ordered in a particular way, and the interval between stages 1 and 2 is long (14-days), the A-B and B-shock associations are integrated through their chaining at the time of testing with A alone. Thus, number, order and time determine how distinct experiences are integrated in the brain. These findings are discussed with respect to theories of integration and information processing in the medial temporal lobe.

How does the brain integrate experiences that are separated in time? The present study addressed this question using sensory preconditioning protocols in rats. In these protocols, rats integrate an A-B association (e.g., tone-light) formed in stage 1 with a B- shock association (e.g., light-shock) formed in stage 2 to generate fear responses (freezing) when tested with A alone in stage 3. Here we show that the mechanism of integration depends on the number, order and timing of events across the two stages of training. When the events are novel (low number of exposures) and the interval between stages 1 and 2 is short (24 hours), the A-B and B-shock associations are integrated through formation of a mediated A- shock association during stage 2. By contrast, when the events are more familiar (greater number of exposures), ordered in a particular way, and the interval between stages 1 and 2 is long (14-days), the A-B and B-shock associations are integrated through their chaining at the time of testing with A alone. Thus, number, order and time determine how distinct experiences are integrated in the brain. These findings are discussed with respect to theories of integration and information processing in the medial temporal lobe.

Objectives: Unwanted and often distressing intrusive thoughts of infant-related harm are common during the perinatal period and are associated with poorer maternal mental health. The mechanisms linking perinatal intrusive thoughts to mental health remain poorly understood. One proposed avenue is through maladaptive appraisals, yet there currently are no measures capturing perinatal-specific appraisals. The aim of the current study was to develop and validate a novel Perinatal Intrusions Interpretation Index (PIII) to assess negative appraisals related to intrusions of infant-related harm. Methods: 439 people who were 1–6 months postpartum completed 12 items capturing appraisals and an adapted online version of the Postpartum Intrusions Interview. A second validation sample, N = 142 people ≤ 9 months postpartum, completed the final 10-item PIII. Results: Exploratory and confirmatory factor analyses indicated a three-factor structure of the PIII: 1) inflated responsibility, 2) importance of thoughts, and 3) need for control. The total PIII and subscales demonstrated good internal consistency. Higher negative appraisals on the PIII were significantly associated with more frequent and distressing accidental and intentional infant-related harm intrusive thoughts and maladaptive behavioural responses. Intrusion type (accidental versus intentional) moderated the relationship between negative appraisals and intrusion frequency and distress, and frequency of behavioural responses. Conclusions: The PIII is a reliable and valid scale to assess negative appraisals of infant-related harm intrusions. Negative appraisals may be a cognitive risk factor for perinatal intrusions to progress from normative to functionally impairing, offering a modifiable target for the prevention and treatment of perinatal anxiety disorders.

We previously identified the roles of the basolateral amygdala complex (BLA) and perirhinal cortex (PRh) in sensory preconditioning in male and female rats (Wong et al., 2025). Here, we used variations of a sensory preconditioning protocol to test a general theory that the BLA and PRh represent focal and peripheral states of attention, respectively. We specifically tested predictions derived from the theory regarding when learning about a stimulus that signals danger will be disrupted by BLA or PRh infusions of the N -methyl-D-aspartate receptor (NMDAR) antagonist, DAP5. Consistent with the theory, the effects of these infusions depended on the novelty/familiarity of the conditioned stimulus, as well as the manner in which it was paired with foot shock. When a stimulus was novel, its conditioning required NMDAR-activation in the BLA and not the PRh, regardless of whether the stimulus and shock were presented contiguously or separated in time. When a pre-exposed and, thereby, familiar stimulus was presented contiguously with shock, its conditioning again required NMDAR-activation in the BLA and not the PRh. However, when a pre-exposed stimulus was indirectly paired with shock – because it was associatively activated at the time of shock or separated from the shock by another stimulus – its conditioning required NMDAR-activation in the PRh and not the BLA. These findings are discussed in relation to theories of information processing that distinguish between focal and peripheral states of attention/memory, and past studies that have examined the substrates of learning and memory in the PRh and BLA.

While the infralimbic cortex (IL) is recognized as critical for behavioral inhibition, the content of the inhibitory memories stored in this region remains elusive. To probe this content, we examined some of the conditions that allow retrieval and facilitation of an inhibitory memory stored in the IL using optogenetic stimulation in female and male rats. We found that IL stimulation did not facilitate an initial fear extinction session. However, prior experience with fear extinction enabled IL stimulation to facilitate subsequent fear extinction. Importantly, the facilitative effects of IL stimulation were not limited to fear extinction experience, as prior exposure to backward fear conditioning also enabled IL stimulation to enhance later fear extinction. The effects were stimulus-specific and did not depend on the motivational context present during the prior experience, as backward appetitive conditioning allowed IL stimulation to facilitate later fear extinction. Additional experiments ruled out stimulus familiarity as an explanation for the facilitative effects of IL stimulation and demonstrated that IL-mediated facilitations occur in procedures other than fear extinction. Together, these findings demonstrate that the IL stores inhibitory memories that are extremely flexible since they can be retrieved and used across many inhibitory procedures and distinct motivational contexts. These features establish the IL as a critical hub for the flexible application of inhibitory knowledge that allows adaptive responses in dynamic environments.

While the infralimbic cortex (IL) is recognized as critical for behavioral inhibition, the content of the inhibitory memories stored in this region remains elusive. To probe this content, we examined some of the conditions that allow retrieval and facilitation of an inhibitory memory stored in the IL using optogenetic stimulation in female and male rats. We found that IL stimulation did not facilitate an initial fear extinction session. However, prior experience with fear extinction enabled IL stimulation to facilitate subsequent fear extinction. Importantly, the facilitative effects of IL stimulation were not limited to fear extinction experience, as prior exposure to backward fear conditioning also enabled IL stimulation to enhance later fear extinction. The effects were stimulus-specific and did not depend on the motivational context present during the prior experience, as backward appetitive conditioning allowed IL stimulation to facilitate later fear extinction. Additional experiments ruled out stimulus familiarity as an explanation for the facilitative effects of IL stimulation and demonstrated that IL-mediated facilitations occur in procedures other than fear extinction. Together, these findings demonstrate that the IL stores inhibitory memories that are extremely flexible since they can be retrieved and used across many inhibitory procedures and distinct motivational contexts. These features establish the IL as a critical hub for the flexible application of inhibitory knowledge that allows adaptive responses in dynamic environments.

This study used variations of a sensory preconditioning protocol in male and female rats to test a theory that the basolateral amygdala complex (BLA) and perirhinal cortex (PRh) represent focal and peripheral states of attention, respectively. It specifically tested predictions derived from the theory regarding when learning about a stimulus that signals danger will be disrupted by BLA or PRh infusions of the N-methyl-D-aspartate receptor (NMDAR) antagonist, DAP5. Consistent with the theory, the effects of these infusions depended on the novelty/familiarity of the conditioned stimulus as well as the manner in which it was paired with foot shock. When a stimulus was novel, its conditioning required activation of NMDAR in the BLA and not the PRh (Experiments 2A and 2B) regardless of whether the stimulus-shock pairings were contiguous or separated in time. When a pre-exposed and, thereby, familiar stimulus was presented contiguously with shock, its conditioning again required activation of NMDAR in the BLA and not the PRh (Experiments 1A, 1B, 3A and 3B). However, when a pre-exposed stimulus was indirectly paired with shock - because it was associatively activated at the time of shock or separated from the shock by another stimulus - its conditioning required activation of NMDAR in the PRh and not the BLA (Experiments 1A, 1B, 3A and 3B). These findings are discussed in relation to theories of information processing that distinguish between focal and peripheral states of attention/memory, and past studies that have examined the substrates of learning and memory in the PRh and BLA.

While the infralimbic cortex (IL) is recognized as critical for behavioral inhibition, the content of the inhibitory memories stored in this region remains elusive. To probe this content, we examined some of the conditions that allow retrieval and facilitation of an inhibitory memory stored in the IL using optogenetic stimulation in female and male rats. We found that IL stimulation did not facilitate an initial fear extinction session. However, prior experience with fear extinction enabled IL stimulation to facilitate subsequent fear extinction. Importantly, the facilitative effects of IL stimulation were not limited to fear extinction experience, as prior exposure to backward fear conditioning also enabled IL stimulation to enhance later fear extinction. The effects were stimulus-specific and did not depend on the motivational context present during the prior experience, as backward appetitive conditioning allowed IL stimulation to facilitate later fear extinction. Additional experiments ruled out stimulus familiarity as an explanation for the facilitative effects of IL stimulation and demonstrated that IL-mediated facilitations occur in procedures other than fear extinction. Together, these findings demonstrate that the IL stores inhibitory memories that are extremely flexible since they can be retrieved and used across many inhibitory procedures and distinct motivational contexts. These features establish the IL as a critical hub for the flexible application of inhibitory knowledge that allows adaptive responses in dynamic environments.

This study used variations of a sensory preconditioning protocol in male and female rats to test a theory that the basolateral amygdala complex (BLA) and perirhinal cortex (PRh) represent focal and peripheral states of attention, respectively. It specifically tested predictions derived from the theory regarding when learning about a stimulus that signals danger will be disrupted by BLA or PRh infusions of the N-methyl-D-aspartate receptor (NMDAR) antagonist, DAP5. Consistent with the theory, the effects of these infusions depended on the novelty/familiarity of the conditioned stimulus as well as the manner in which it was paired with foot shock. When a stimulus was novel, its conditioning required activation of NMDAR in the BLA and not the PRh (Experiments 2A and 2B) regardless of whether the stimulus-shock pairings were contiguous or separated in time. When a pre-exposed and, thereby, familiar stimulus was presented contiguously with shock, its conditioning again required activation of NMDAR in the BLA and not the PRh (Experiments 1A, 1B, 3A and 3B). However, when a pre-exposed stimulus was indirectly paired with shock - because it was associatively activated at the time of shock or separated from the shock by another stimulus - its conditioning required activation of NMDAR in the PRh and not the BLA (Experiments 1A, 1B, 3A and 3B). These findings are discussed in relation to theories of information processing that distinguish between focal and peripheral states of attention/memory, and past studies that have examined the substrates of learning and memory in the PRh and BLA.