A cellular defense memory imprinted by early life toxic stress

Abstract

Stress exposure early in life is implicated in various behavioural and somatic diseases. experiences during the critical perinatal period form permanent, imprinted memories promoting adult survival.Although imprinting is widely recognized to dictate behaviour, whether it actuates specific transcriptional responses at the cellular level is unknown. Here we report that in response to early life stresses, Caenorhabditis elegans nematodes form an imprinted cellular defense memory. We show that exposing newly-born worms to toxic antimycin A and paraquat, respectively, stimulates the expression of toxin-specific cytoprotective reporters. Toxin exposure also induces avoidance of the toxincontaining bacterial lawn. in contrast, adult worms do not exhibit aversive behaviour towards stressassociated bacterial sensory cues. However, the mere re-encounter with the same cues reactivates the previously induced cytoprotective reporters. Learned adult defenses require memory formation during the L1 larval stage and do not appear to confer increased protection against the toxin. Thus, exposure of C. elegans to toxic stresses in the critical period elicits adaptive behavioural and cytoprotective responses, which do not form imprinted aversive behaviour, but imprint a cytoprotective memory. Our findings identify a novel form of imprinting and suggest that imprinted molecular defenses might underlie various pathophysiological alterations related to early life stress.Associative learning ensures rapid, efficient adaptation to already experienced, re-emerging conditions 1,2 . Re-encountering sensory cues associated with a relevant past experience retrieves the memory and elicits a complex response corresponding to the past incident. Associative memories are generally transient. In contrast, a peculiar learning process takes place early in life during a specific time window, called the critical or sensitive period and gives rise to especially persistent memories. Hence the name, imprinting, which was coined by Konrad Lorenz who observed that newly hatched birds created a strong bond with the first moving object seen 3 . Besides visual cues, olfactory memories driving adult behaviours have been recognized in several vertebrate species, including the homing of salmons to reproduce in the creek they were born 4 and preference for odours associated perinatally with food in mammals 5,6 . Hence, imprinting serves as the biological basis of secure, long lasting attachment to qualities essential for individual and/or species' survival. In further support of the profound, life-long impact of imprinted memories, a growing body of evidence shows that facing adversity in the critical period is connected to different cognitive and affective disorders and are accompanied by brain epigenetic, structural and endocrine alterations 7-9 . On the other hand, early life stress predispose to increased telomere erosion, metabolic and cardiovascular diseases in adulthood ultimately affecting healthy lifespan 10-12 . Some of the open questions emerging from th...

Alanine tRNAs Translate Environment Into Behavior in Caenorhabditis elegans

“…The AWC olfactory neurons are responsive to a high number of chemically different molecules that include the three chemoattractants BA, CI and IA used in this study (Bargmann et al, 1993). Only the developing first larval stage L1 can be imprinted by attractive (this study), aversive (Jin et al, 2016), or toxic stress (Gecse et al, 2019) signals present in worm's environment. Environmentresponsive mechanisms must be present at this stage to adapt future worm's behaviors through up or down-regulation of genes expressed in chemosensory neurons.…”

“…(E) In the absence of imprinting, as in elpc-1 mutants, odorants will stably decrease the innate worm responses for these odorants. environmental conditions (Hall et al, 2010;Jin et al, 2016;Hong et al, 2017;Gecse et al, 2019). Imprinting chemo-attractive cues is an innate behavior taking place during this period of development.…”

Toxic stress-specific cytoprotective responses regulate learned behavioral decisions in C. elegans

“…Such cytoprotective stress and detoxification responses form a cellular defense network and cooperate to ensure survival, stress tolerance, immunity, and longevity [ 3 , 12 ]. A few studies reported on the neural “top-down” control of cellular cytoprotective responses in worms [ 20 , 41 , 47 ], but a “bottom-up” direction of communication is much less explored. Such regulation has only recently been observed in the case of the inhibition of P. aeruginosa avoidance by intestinal pmk-1 [ 35 ].…”

“…The “fight-or-flight” response is an evolutionarily conserved adaptive response to stress, originally coined for the vertebrate neuroendocrine system [ 2 ]. Recent studies in C. elegans showed the co-occurrence of behavioral “flight” responses with molecular stress and immune “fight” responses combating stress [ 18 – 20 ]. Our studies in addition to an independent confirmation of the co-occurrence of these responses, reveal a regulatory link between intracellular cytoprotective responses and behavioral tolerance, suggesting a coordinated action of the fight and the flight responses to combat toxic stress.…”

“…Recent studies in C. elegans , including ours, provided evidence that pathogen- and toxin-induced stresses simultaneously stimulate cytoprotective responses and aversive behavior [ 18 – 20 ]. In this study, we set out to investigate how the induction of systemic cytoprotective molecular defenses influences stress-induced aversive behavior and learned behavioral decisions.…”