Contributions of associative and non-associative learning to the dynamics of defensive ethograms.
Defensive behavior changes based on threat intensity, proximity, and context of exposure, and learning about danger-predicting stimuli is critical for survival. However, most Pavlovian fear conditioning paradigms focus only on freezing behavior, obscuring the contributions of associative and non-associative mechanisms to dynamic defensive responses. To thoroughly investigate defensive ethograms, we subjected male and female adult C57BL/6 J mice to a Pavlovian conditioning paradigm that paired footshock with a serial compound stimulus (SCS) consisting of distinct tone and white noise (WN) stimulus periods. To investigate how associative and non-associative mechanisms affect defensive responses, we compared this paired SCS-footshock group with four control groups that were conditioned with either pseudorandom unpaired presentations of SCS and footshock, shock only, or reversed SCS presentations with inverted tone-WN order, with paired or unpaired presentations. On day 2 of conditioning, the paired group exhibited robust freezing during the tone period with switching to explosive jumping and darting behaviors during the WN period. Comparatively, the unpaired and both reverse SCS groups expressed less tone-induced freezing and rarely showed jumping or darting during WN. Following the second day of conditioning, we observed how defensive behavior changed over two extinction sessions. During extinction, the tone-induced freezing decreased in the paired group, and mice rapidly shifted from escape jumping during WN to a combination of freezing and darting. The unpaired, unpaired reverse, and shock-only groups displayed defensive tail rattling and darting during the SCS, with minimal freezing and jumping. Interestingly, the paired reverse group did not jump to WN, and tone-evoked freezing was resistant to extinction. These findings demonstrate that non-associative factors promote some defensive responsiveness, but associative factors are required for robust cue-induced freezing and high-intensity flight expression.
Le QE
，Hereford D
，Borkar CD
，Aldaco Z
，Klar J
，Resendez A
，Fadok JP
... -
《eLife》
Stress-enhanced fear learning can be reduced with unconditional stimulus deflation with constraints.
Exposure to extreme stress can negatively impact behavior and lead to prolonged fear sensitization. These processes can be studied in the lab using stress-enhanced fear learning (SEFL), where prior exposure to inescapable stress exacerbates later contextual fear conditioning. A common method to reduce conditional fear is through extinction, where a conditional stimulus once paired with an unconditional (US; e.g., a footshock) is presented alone. Previous research shows that extinction learning may not be as effective at reducing fear behavior in rodents previously exposed to stress, mirroring similar extinction impairments observed in aged rodents. Weak-shock exposure (termed US deflation) following conditioning with a strong shock has been proposed to be an alternative to extinction where presentations of weaker versions of the US would work to modify the original fear memory rather than create a new memory as in extinction and thus more precisely target the original context fear memory. While effective under normal conditions, it has yet to be studied how effective US deflation is at reducing stress-enhanced context fear. Here we aimed to test if US deflation could reduce fear in a SEFL paradigm and identify any constraints of this effect. Following 15 inescapable footshocks or matched chamber exposure, male and female Long Evans rats received 1 context-shock pairing or 5 context-shock pairings in a novel context. The next day, they were given either 10 weak footshocks (US deflation) or extinction before behavioral testing. Following training with 1 context-shock pairing, both US deflation and extinction functioned similarly in reducing freezing behavior of stressed rodents. However, following 5 context-shock pairings, only the unstressed rodents displayed a significant decrease in fear behavior, suggesting that prior stress coupled with more robust conditioning can limit the efficacy of US deflation in reducing fear behavior. Finally, we replicated the SEFL effect in aged rodents and found that they showed a significant decrease in stress-enhanced fear learning following US deflation, whereas our previous research showed impairments of traditional extinction in aged rodents. Together, these results suggest that US deflation can reduce SEFL in both adult and aged rodents following a single context-shock pairing, with additional pairings rendering this procedure ineffective at mitigating the effects of prior stress.
Brooks JB
，Robinson PK
，Warner S
，Halder P
，Trask S
... -
《-》
Impacts of linseed oil diet on anxiety and memory extinction after early life stress: A sex-specific analysis of mitochondrial dysfunction, astrocytic markers, and inflammation in the amygdala.
Early exposure to stressors affects how the organism reacts to stimuli, its emotional state throughout life, and how it deals with emotional memories. Consequently, it may affect susceptibility to psychopathology later in life. We used an animal model of early stress by maternal separation to study its potential impact on the extinction of aversive memories and anxiety-like behavior in adulthood, as well as its effects on mitochondrial functionality, inflammatory and astrocytic markers in the amygdala. We also assessed whether a diet enriched with linseed oil, known for its high content in omega-3 fats, could be used to attenuate the behavioral and neurochemical effects of early stress. Litters of Wistar rats were divided into controls (intact) or subjected to maternal separation (MS). They were subdivided into two groups receiving isocaloric diets enriched in soy or linseed oils at weaning. In adulthood, the animals were exposed to the open field and the elevated plus maze, to evaluate exploratory activity and anxiety-like behavior. They were also trained in a context of fear conditioning, and afterward subjected to an extinction session, followed by a test session to evaluate the extinction memory. Amygdalae were evaluated for inflammatory cytokines (interleukin (IL)-1beta, IL-6, and tumor-necrose factor (TNF)-alpha), mitochondrial functionality, and astrocyte markers (glial fibrillary acidic protein - GFAP, S100B, and glutamine synthetase activity). MS induced anxiety-like behavior in the elevated plus-maze, which was reversed by a diet enriched in linseed oil offered from weaning. When testing the memory of an extinction session of fear conditioning, MS animals showed more freezing behavior. MS males receiving a linseed oil-enriched diet had lower functional mitochondria in the amygdala. In addition, MS led to increased inflammatory cytokines, particularly IL-1beta, and the diet enriched in linseed oil further increased these levels in MS animals. MS also increased S100B levels. These results point to a higher emotionality presented by MS animals, with higher levels of inflammatory cytokines and S100B. While a diet enriched in linseed oil attenuated anxiety-like behavior, it further altered amygdala IL-1beta and reduced mitochondria functionality, particularly in males. MS also increased glutamine synthetase activity in the amygdala, and this effect was higher when the animals received a diet enriched in linseed oil, particularly in females. In conclusion, these results point to MS effects on emotional behavior, and neurochemical alterations in the amygdala, with sex-specific effects. Although a diet enriched in linseed oil appears to be able to reverse some of MS behavioral effects, these results must be considered with caution, since biochemical parameters could be worsened in MS animals receiving a linseed oil-enriched diet. This knowledge is important for the understanding of mechanisms of action of strategies aiming to reverse early stress effects, and future studies are warranted to determine possible interventions to promote resilience.
Andressa Caetano R
，Alves J
，Smaniotto TA
，Daroda Dutra F
，de Assis EZB
，Soares Pedroso L
，Peres A
，Machado AG
，Krolow R
，Maciel August P
，Matté C
，Seady M
，Leite MC
，Machado BG
，Marques C
，Saraiva L
，de Lima RMS
，Dalmaz C
... -
《-》
ResearchGate
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钛学术
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