Biology subjects

Bradfield, L. A.

Publications and source records attributed to Bradfield, L. A..

5 recordsLinked to original sources

bioRxiv2026

Contingency degradation overwrites initial learning and depends on lateral orbitofrontal cortex

Relapse after treatment for various mental health disorders has been linked to tendency for reductions in responding to increase over time or following re-exposure to motivating stimuli. Here we show that, in rats, responding reduced through non-contingent outcome delivery does not recover in these ways, and that this learning depends on an intact lateral orbitofrontal cortex. These findings suggest that contingency degradation overwrites original learning which may support the development of relapse-resistant behavioural interventions.

animal behavior and cognition↗

bioRxiv2024

Hippocampal neuroinflammation causes sex-specific disruptions in instrumental conditioning, Pavlovian approach, and neuronal excitation

Hippocampal neuroinflammation is present in multiple diseases and disorders that impact motivated behaviour in a sex-specific manner, but whether neuroinflammation alone is sufficient to disrupt such behaviour is unknown. We investigated this question here using mice. First, the application of an endotoxin to primary cultures containing only hippocampal neurons did not affect their activation. However, when the same endotoxin was applied to mixed neuronal/glial cultures it did increase neuronal activation, providing initial indications of how it might be able to effect behavioural change. We next demonstrated neuroinflammatory effects on behaviour directly, demonstrating that intra-hippocampal administration of the same endotoxin increased locomotor activity and accelerated goal-directed learning in both male and female mice. In contrast, hippocampal neuroinflammation caused sex-specific disruptions to the acquisition of instrumental actions and to Pavlovian food-approach memories. Finally, we showed that hippocampal neuroinflammation had a sexually dimorphic effect on neuronal activation: increasing it in females and decreasing it in males.

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↗

bioRxiv2020

Medial Orbitofrontal Cortex Regulates Instrumental Conditioned Punishment, but not Pavlovian Conditioned Fear

Bidirectionally aberrant medial orbitofrontal cortical (mOFC) activity has been consistently linked with compulsion and compulsive disorders. Although rodent studies have established a causal link between mOFC excitation and compulsive-like actions, no such link has been made with mOFC inhibition. Here we use excitotoxic lesions of mOFC to investigate its role in sensitivity to punishment; a core characteristic of many compulsive disorders. In our first experiment, we demonstrated that mOFC lesions prevented instrumental conditioned punishment learning in a manner that could not be attributed to differences in Pavlovian conditioned fear. We then showed that increasing the frequency of punishing outcomes allowed mOFC-lesioned animals to overcome their initial deficit. Our second experiment demonstrated that the retrieval of instrumental punishment is also mOFC-dependent, as mOFC lesions prevented the extended retrieval of punishment contingencies relative to shams. In contrast, mOFC lesions did not prevent the re-acquisition of conditioned punishment that was learned prior to lesions being administered. Together, these results reveal that the mOFC does indeed regulate punishment learning and retrieval in a manner that is disassociated from any role in Pavlovian fear learning. These results imply that aberrant mOFC activity may contribute to the punishment insensitivity that is observed across multiple compulsive disorders.

neuroscience↗

bioRxiv2019

Goal-directed action transiently depends on action space

Rats use spatiotemporal features of the environment to navigate to a goal, but whether representations of action space are necessary for non-navigational goal-directed actions is unknown. We addressed this question by assessing goal-directed action control across contexts and under hippocampal inactivation and found that such actions do indeed rely on a representation of action space but only immediately after initial acquisition.\n\nOne Sentence SummaryGoal-directed actions depend on a hippocampal representation of action space immediately after initial encoding but not after a delay.

animal behavior and cognition↗