Paternal early life stress exerts intergenerational effects on male C57Bl/6J offspring risk-taking behaviors and predator scent-induced c-Fos expression

Abstract

Paternal preconceptional health factors, such as exposures to stress, diet and exercise, have been found to significantly influence offspring phenotypes in a range of animal models. Preclinical studies have provided evidence that paternal stress is associated with increased stress responsivity and anxiety-related traits, particularly in male offspring. It was previously reported that a paternal history of maternal separation (MS) led to male offspring (PatMS) displaying reduced cautious behavior during exploration of a novel environment. The neural basis for that absence of behavioral moderation is unclear. Here, we investigated the adaptive behavioral responses of control and PatMS male offspring in the predator odour risk-assessment task (PORT). PatMS mice failed to moderate their behaviors in the presence of a predator odour trimethylthiazoline (TMT). c-Fos mapping revealed reduced cellular activation in fear-regulating brain regions of PatMS mice, such as in the cingulate cortex, dentate gyrus of the hippocampus, and the basolateral amygdala. Expression of the paternally imprinted gene Grb10 (previously identified as a key molecular regulator of risk-taking behavior) was unaltered in PatMS mice. However, other paternal imprinted genes such as Igf2 and PEG3 were differentially expressed in PatMS mice. Overall, our study provides the first evidence of an intergenerational influence of preconceptional paternal stress exposure on offspring brain function relevant to risk-taking behavior, which is also independent of Grb10 gene expression.

Inter- and transgenerational heritability of preconception chronic stress or alcohol exposure: Translational outcomes in brain and behavior

“…In tandem with the exploratory behavior these offspring showed, increased stretch-attend posture might indicate a risk assessment process, ( Holly et al, 2016 ) and the authors interpreted their findings as an indication that the mice were showing reduced caution ( Mansuy et al, 2011 ; Rodgers and Dalvi, 1997 ). This interpretation is consistent with the previously-discussed findings of impaired risk assessment in PPS offspring from a maternal separation paradigm ( Thivisol Ulysse et al, 2023 ) and suggests a greater pattern of intergenerational early life stress-induced effects on risk-taking behavior. Female offspring of MSUS-exposed mouse dams have also shown increased stretch-attend posture in the open arms of the EPM, as well as increased percent distance traveled in open arms of the EPM, but no differences were found in the free exploratory paradigm ( Mansuy et al, 2011 ).…”

“…Repeated OFT in one study led authors to interpret their findings as a behavioral control deficit in response to novelty ( Franklin et al, 2010 ). Similar to this interpretation, a 2023 study using maternal separation (not the full MSUS paradigm) found the mice displayed impaired risk assessment in response to a predator odor and increased dominance in the social dominance tube task, both in male offspring ( Thivisol Ulysse et al, 2023 ). One study conducted delay-discounting and behavioral sequencing tasks, which revealed enhanced goal-directed behaviors and behavioral flexibility in adult female offspring ( Gapp et al, 2014a ).…”

Bridging Species and Disciplines: Incorporating Sociological Frameworks into Animal Models of Addiction

“…Research involving paternal early life stress in animal models, such as in C57Bl/6 J mice, has provided evidence of intergenerational effects on offspring behavior. This includes changes in risk-taking behaviors and brain function relevant to addiction, independent of specific gene expression [85].…”

Effects of paternal arachidonic acid supplementation on offspring behavior and hypothalamus inflammation markers in the mouse

“…Most studies have focused on the effects of maternal high-fat diet (HFD) during mating, pregnancy, and lactation and have demonstrated adverse effects on anxiety levels not only in F1 offspring, but also in F2 and possibly F3 generations [42,43]. Although corresponding data pertaining to paternal exposure is limited [20], the association of paternal stress, trauma, HFD and environmental toxins with aberrant offspring behaviors, such as anxiety, risk taking, memory deficits and social behavior has been documented [44][45][46][47][48][49]. Our data are consistent with the general observation that paternal exposure can alter the immune response, although with complex outcomes: on the one hand, offspring of male mice exposed to sublethal amounts of C. albicans inherited an augmented response to infections compared with progeny of untreated males [50].…”