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Ketamine is a non-competitive N-methyl-D-aspartate (NMDA)-channel blocker that has recently shown promise in the treatment of major depressive disorder, distinguishing itself from classical anti-depressants through its rapid and lasting effects when given at sub-anaesthetic doses. Animal models of depression are commonly used to research individual mechanisms of action and this literature review aimed to investigate how ketamine influences BDNF-TrkB neurotransmission in the hippocampus and prefrontal cortex within animal models of depression. Reduced levels of BDNF and TrkB-transmission, as well as downstream signalling, are common in both humans experiencing depression and in rodent models of depression, and ketamine was found to counteract this reduction in the majority of studies reviewed. In the majority of studies ketamine’s anti-depressant actions were viewed to be at least partially connected to its effects on BDNF-TrkB neurotransmission. This was supported by the anti-depressant effects being readily blocked by pharmacological inhibition of TrkB. Inhibition also blocked the downstream neurobiological changes associated with ketamines anti-depressant effects. / Ketamin är en icke-kompetitiv N-methyl-D-aspartate (NMDA)-kanal antagonist som nyligen har visat lovande resultat i behandling av depression. Substansen särskiljer sig från klassiska antidepressiva läkemedel genom att dess effekt infinner sig snabbt och kvarstår under en längre period om det ges i låga doser. Djurmodeller av depression används för att undersöka individuella mekanismer relaterade till depression och denna litteraturstudie ämnade att undersöka hur ketamin påverkar BDNF-TrkB signallering inom hippocampus och prefrontala cortex i djurmodeller av depression. Minskade nivåer av BDNF och TrkB-signalering är vanligt förekommande både hos männsikor med depression och i djurmodeller av depression. I majoriteten av studierna återställde ketamin nivåerna av BDNF och TrkB-signalering till normala värden. Dess antidepressiva effekt kopplades till denna signalväg eftersom farmakologisk inhibering av TrkB i majoriteten av studierna resulterade i att den anti-depressiva effekten uteblev. Inhiberingen blockerade även nedströms neurobiologiska förändringar som anses kopplade till ketamins antidepressiva effekter.

The present study assessed the impact of aging on cognitive functioning over six to 16 years in exceptionally healthy individuals (20 to 79 years) drawn from the Baltimore Longitudinal Study of Aging. The first study (N = 380 women, 757 men) examined the relationship between age and speed of processing as measured by five reaction time (RT) tasks (simple reaction time to complex reaction time involving varying amounts of inhibitory and working memory processing). Unlike previous research, this study additionally assessed the impact of processing speed, working memory, inhibitory processing, and interference RT measures in predicting future performance 6-16 years later (N=103) on (1) mental status (Blessed Information-Memory-Concentration, Mini-Mental State Examination), and prefrontal mediated neuropsychological tests (Trail Making A and B; verbal and category fluency; WAIS digits forward and backwards, California Verbal Learning Test proactive interference index). Regression analyses assessed which theoretical approach, speed of processing (Salthouse, 1996) or prefrontal cortex (Hasher & Zacks, 1988; West, 1996), better explained cognitive change. Age-related cognitive slowing was observed for initial RT tasks. Especially among the oldest studied (62-79 years of age), slower speed of processing was accelerated by task complexity. Increases in response time were substantially steeper for older as opposed to younger participants. Men were faster than women were on simple RT and a RT task that involved inhibitory processing. A 6-9 year age decline in speed of processing only occurred among individuals over 60 years. RT omission and commission errors showed similar results. Hierarchical regression analyses determined that RT tasks involving inhibitory control, working memory and interference were most predictive of future prefrontal-mediated cognitive performance (Trail Making B, digit span backwards, letter and category fluency). Prediction of the prefrontal outcome measures of Trail Making A and digit span forward performance from simple reaction time was mediated by the RT measures (inhibitory control, working memory and interference), but not the other way around. Thus, the data most strongly support the Inhibitory Deficit (Hasher & Zacks, 1988) and Prefrontal Cortex Function (West, 1996) theories. There was little support for the processing speed theory (Salthouse, 1996). / Ph. D.

Organisms must continuously navigate complex environments, balancing the drive to seek rewards with the need to avoid potential threats. This tradeoff between approach and avoidance behaviors, known as approach-avoidance conflict, is a critical determinant of survival. The medial prefrontal cortex (mPFC) plays a key role in regulating these behaviors, with the ventromedial (vmPFC) and dorsomedial components thought to suppress and promote, respectively, behavioral responses to threats. Within the vmPFC, neural populations expressing the opioid peptide dynorphin (Dyn) and its receptor, the kappa opioid receptor (KOR), have been implicated in stress responses. However, the specific role of the vmPFC Dyn system in encoding threat-related information and shaping behavioral responses remains largely unexplored. To address this, we employed a multi-faceted approach, utilizing fiber photometry, calcium imaging, shRNA-mediated knockdown, and DREADD-mediated inhibition to investigate the vmPFC Dyn system in various threat-related paradigms. These included the platform-mediated avoidance (PMA) task, which assesses approach-avoidance conflict; the repeated looming disk test, a pain-free model of innate fear suppression; and standard fear conditioning, a well-established paradigm for studying learned fear responses. Our findings reveal that while the vmPFC Dyn system is not differentially regulated under non-threatening baseline conditions, it is actively recruited upon threat exposure. Fiber photometry recordings during the PMA task showed that vmPFC Dyn neurons bidirectionally signal features related to approach and avoidance behaviors in the presence of threat. Furthermore, shRNA-mediated downregulation of Dyn in the vmPFC led to enhanced avoidance in the repeated looming disk test, indicating that Dyn is necessary for suppressing avoidance in this context. Calcium imaging of the pan-neuronal vmPFC population in conjunction with Dyn knockdown revealed that loss of Dyn impairs cortical activity, as evidenced by reduced synchrony and decreased performance of a logistic regression decoder. These findings suggest that Dyn plays a critical role in shaping the activity of vmPFC neurons during threat processing. Taken together, our results highlight a specific role for the vmPFC Dyn system in toggling threat-driven behavioral responses, particularly in the context of approach-avoidance conflict. By demonstrating how Dyn shapes both behavior and neural activity in the vmPFC during threat exposure, this study provides novel insights into an understudied area of opioidergic circuitry. Moreover, our findings contribute to a deeper understanding of how distinct cell types within the vmPFC encode threat-related features to promote or suppress avoidance behaviors, shedding light on the neural mechanisms underlying adaptive responses to environmental challenges.