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[Preprint]. 2023 Apr 28:2023.04.27.538622.
doi: 10.1101/2023.04.27.538622.

Social aging trajectories are sex-specific, sensitive to adolescent stress, and most robustly revealed during social tests with familiar stimuli

Christopher Figueroa  1 , Erin L Edgar  1 , J M Kirkland  1 , Ishan Patel  1 , David N King'uyu  1 , Ashley M Kopec  1
Affiliations

Social aging trajectories are sex-specific, sensitive to adolescent stress, and most robustly revealed during social tests with familiar stimuli

Christopher Figueroa et al. bioRxiv. .

Abstract

Social networks and support are integral to health and wellness across the lifespan, and social engagement may be particularly important during aging. However, social behavior and social cognition decline naturally during aging across species. Social behaviors are in part supported by the 'reward' circuitry, a network of brain regions that develops during adolescence. We published that male and female rats undergo adolescent social development during sex-specific periods, pre-early adolescence in females and early-mid adolescence males. Although males and females have highly dimorphic development, expression, and valuation of social behaviors, there is relatively little data indicating whether social aging is the same or different between the sexes. Thus, we sought to test two hypotheses: (1) natural social aging will be sex-speciifc, and (2) social isolation stress restricted to sex-specific adolescent critical periods for social development would impact social aging in sex-specific ways. To do this, we bred male and female rats in-house, and divided them randomly to receive either social isolation for one week during each sex's respective critical period, or no manipulation. We followed their social aging trajectory with a battery of five tests at 3, 7, and 11 months of age. We observed clear social aging signatures in all tests administered, but sex differences in natural social aging were most robustly observed when a familiar social stimulus was included in the test. We also observed that adolescent isolation did impact social behavior, in both age-independent and age-dependent ways, that were entirely sex-specific. Please note, this preprint will not be pushed further to publication (by me, AMK), as I am leaving academia. So, it's going to be written more conversationally.

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Conflict of interest statement

Author Declarations: AMK designed the experiments. CF, JMK, IP, and DNK performed the experiments. ELE and AMK analyzed the experiments. AMK wrote the manuscript. All authors edited the manuscript. The authors declare no conflicts of interest.

Figures

Fig. 1:
Fig. 1:. Social exploration decreases, and object exploration increases with age in both sexes in a Social vs. Object choice test
At three different ages in adulthood, rats are placed in a two-chamber compartment with free access to explore a novel adult sex-matched conspecific or a novel nonsocial object for 5 mins. In both sexes, (A) social exploration decreased with age, most significantly from 3 to 7 mos, and (B) object exploration increased with age, most significantly from 7 to 11 mos. In the latter, females explored the object stimulus more overall than males. (C) Both sexes decreased the percentage of time spent in social exploration while in the social half of the arena from 3 to 11 mos, while females had overall higher percentages of social exploration in the social half relative to males. In contrast, (D) the percentage of time spent in object exploration while in the object half of the arena decreased from 3 to 7 mos before rebounding at 11 mos. This trend was observed in both sexes. n=6–10/sex; test was repeated in the same rats at each time point. Histograms depict average ± SEM. Italicized bottom left text indicates statistically significant (*p<0.05) main effects and interactions. All statistical details can be found in Table 1.
Fig. 2:
Fig. 2:. Novel and familiar social exploration decreases with age in sex-specific ways in a Social Novelty Preference choice test
At three different ages in adulthood, rats are placed in a two-chamber compartment with free access to explore a novel adult sex-matched conspecific or a familiar sex- and age-matched cage mate for 5 mins. (A) In males, but not females, novel social exploration decreased linearly with age. (B) In both sexes, familiar social exploration decreased with age, but by a greater degree from 3 to 7mo in females due to a higher 3mo exploratory baseline. (C) Both sexes decreased the percentage of time spent in novel social exploration while in the novel social half of the arena from 3 to 11 mos, while females had overall higher percentages of novel social exploration in the social half relative to males. Similarly, (D) both sexes decreased the percentage of time spent in familiar social exploration while in the familiar social half of the arena from 3 to 7 mos. n=6–10/sex; test was repeated in the same rats at each time point. Histograms depict average ± SEM. Italicized bottom left text indicates statistically significant (*p<0.05) main effects and interactions. All statistical details can be found in Table 2.
Fig. 3:
Fig. 3:. Free social behavior towards a novel juvenile changes sex-specifically with age
At three different ages in adulthood, rats are placed in a clean cage with a novel sex-matched juvenile rat (~P25–26) and recorded for 5 mins. Behavior of the experimental rat was coded as Active, Passive, Nonsocial Contact, or Nonsocial Attention as depicted in Supp. Fig. 1. (A-B) Active and passive social behaviors toward the juvenile decreased with age in both sexes. (C) In males, but not females, nonsocial contact increased with age, most significantly from 3 to 7 mo, while (D) nonsocial attention did not significantly change with age in either sex. n=6–10/sex; test was repeated in the same rats at each time point. Histograms depict average ± SEM. Italicized bottom left text indicates statistically significant (*p<0.05) main effects and interactions. All statistical details can be found in Table 3.
Fig. 4:
Fig. 4:. Free social behavior towards a familiar cage mate changes sex-specifically with age
At three different ages in adulthood, age- and sex-matched cage mates are separated for ~20mins and then placed together in a clean cage and recorded for 5 mins. Behavior of each rat was coded as Active, Passive, Nonsocial Contact, or Nonsocial Attention as depicted in Supp. Fig. 1. (A) Active social behavior toward a familiar cage mate decreased from 3 to 7mo before rebounding at 11mo. Although both sexes exhibited this pattern, males had overall more active social interaction with their cage mates than females. (B) There was no significant regulation of Passive social interaction with age or by sex. In males, but not females, (C) nonsocial contact increased linearly with age, while (D) nonsocial attention decreased with age, most significantly between 7 and 11mo. n=6–10/sex; test was repeated in the same rats at each time point. Histograms depict average ± SEM. Italicized bottom left text indicates statistically significant (*p<0.05) main effects and interactions. All statistical details can be found in Table 4.
Fig. 5:
Fig. 5:. Aging increases time spent in the inner zone of an Open Field apparatus in both sexes
At three different ages in adulthood, rats are placed in a square open field arena with free access to explore for 5 mins. Time spent in the inner zone of the Open Field, associated with reduced anxiety-like behavior and/or increased exploratory behavior, increased with age in both sexes. Males spend more time in the inner zone overall compared to females. n=6–10/sex; test was repeated in the same rats at each time point. Histograms depict average ± SEM. Italicized bottom left text indicates statistically significant (*p<0.05) main effects and interactions. All statistical details can be found in Table 5.
Fig. 6:
Fig. 6:. Social isolation during sex-specific adolescent critical periods impacts social aging similarly in both sexes in a Social vs. Object choice test
Rats are single-housed during sex-specific critical periods for adolescent social development, P31–37 in males and P23–29 in females, and then re-housed with previous cage mates. At three different ages in adulthood, rats are placed in a two-chamber compartment with free access to explore a novel adult sex-matched conspecific or a novel nonsocial object for 5 mins. (A-B, E-F) In both sexes, social exploration decreased with age and object exploration increased with age. The latter did not reach statistically significance in females, though the same behavior pattern is present. Adolescent isolation did not impact exploration of either stimulus. (C, G) In both sexes, aging decreased the percentage of time spent in social exploration while in the social half of the arena from 3 to 11 mos, with no effect of adolescent isolation. (D, H) In both sexes, adolescent isolation did significantly regulate the percentage of time spent in object exploration while in the object half of the arena. However, in males, adolescent isolation reduces the overall percent of object exploration while in the object half, whereas in females adolescent isolation increases the overall percent of object exploration while in the object half. n=6–10/sex; test was repeated in the same rats at each time point. Histograms depict average ± SEM. Italicized bottom left text indicates statistically significant (*p<0.05) main effects and interactions. “Manip” = adolescent manipulation. All statistical details can be found in Table 1.
Fig. 7:
Fig. 7:. Social isolation during sex-specific adolescent critical periods impacts social aging in females, but not males, in a Social Novelty Preference test
Rats are single-housed during sex-specific critical periods for adolescent social development, P31–37 in males and P23–29 in females, and then re-housed with previous cage mates. At three different ages in adulthood, rats are placed in a two-chamber compartment with free access to explore a novel adult sex-matched conspecific or a familiar age- and sex-matched cage mate for 5 mins. (A-D) In males, exploration of both stimuli and percent exploration while in each respective compartment decreased with age and was not impacted by adolescent isolation. (E, G-H) Similarly, in females, exploration of the novel social stimulus and percent exploration of the novel and familiar social stimuli while in each respective compartment decreased with age independent of adolescent isolation. (F) However, in females only there was an interaction between age and manipulation with respect to familiar social exploration such that adolescent isolation induced lower 3mo exploration than control, and consequently no decline in exploration from 3 to 7mo that is observed in control females. n=6–10/sex; test was repeated in the same rats at each time point. Histograms depict average ± SEM. Italicized bottom left text indicates statistically significant (*p<0.05) main effects and interactions. “Manip” = adolescent manipulation. All statistical details can be found in Table 2.
Fig. 8:
Fig. 8:. Social isolation during sex-specific adolescent critical periods does not impact social aging behavior towards a novel juvenile
Rats are single-housed during sex-specific critical periods for adolescent social development, P31–37 in males and P23–29 in females, and then re-housed with previous cage mates. At three different ages in adulthood, rats are placed in a clean cage with a novel sex-matched juvenile rat (~P25–26) and recorded for 5 mins. Behavior of the experimental rat was coded as Active, Passive, Nonsocial Contact, or Nonsocial Attention as depicted in Supp. Fig. 1. (A-D) In males, Active and Passive social behaviors towards the juvenile decreased with age, Nonsocial contact increased with age, and Nonsocial behavior did not significantly change with age. Adolescent isolation did not impact any of these behavioral measurements. (E-H) In females, Active social interaction towards the juvenile decreased with age, while Passive interaction, Nonsocial Contact, and Nonsocial Attention did not change with age. Similar to males, adolescent isolation did not impact any of these behavioral measurements. n=6–10/sex; test was repeated in the same rats at each time point. Histograms depict average ± SEM. Italicized bottom left text indicates statistically significant (*p<0.05) main effects and interactions. All statistical details can be found in Table 3.
Fig. 9:
Fig. 9:. Social isolation during sex-specific adolescent critical periods sex-specifically impacts social aging behavior towards a familiar cage mate
Rats are single-housed during sex-specific critical periods for adolescent social development, P31–37 in males and P23–29 in females, and then re-housed with previous cage mates. At three different ages in adulthood, age- and sex-matched cage mates are separated for ~20mins and then placed together in a clean cage and recorded for 5 mins at three different ages. Behavior of the rats was coded as Active, Passive, Nonsocial Contact, or Nonsocial Attention as depicted in Supp. Fig. 1. (A-B) In males, Active and Passive social behaviors with familiar cage mates did not significantly change with age. (C) In male Nonsocial Contact behavior there was a age by manipulation interaction such that rats that experienced adolescent isolation had higher Nonsocial Contact than controls at 3mo and thus did not significantly increase this behavior from 3 to 7mo as in control groups. (D) In males, Nonsocial Attention decreased with age independent of adolescent isolation. (E, G-H) In females, there was no significant regulation of Active social interaction, Nonsocial Contact, or Nonsocial Attention by age or adolescent isolation. (F) However, adolescent isolation significantly reduced the overall level of Passive social interaction relative to control females. n=6–10/sex; test was repeated in the same rats at each time point. Histograms depict average ± SEM. Italicized bottom left text indicates statistically significant (*p<0.05) main effects and interactions. “Manip” = adolescent manipulation. All statistical details can be found in Table 4.
Fig. 10:
Fig. 10:. Social isolation during sex-specific adolescent critical periods does not impact time spent in the inner zone of an Open Field apparatus
Rats are single-housed during sex-specific critical periods for adolescent social development, P31–37 in males and P23–29 in females, and then re-housed with previous cage mates. At three different ages in adulthood, rats are placed in a square open field arena with free access to explore for 5 mins. Time spent in the inner zone of the Open Field increased with age in (A) males and (B) females, and adolescent isolation did not impact this behavior in either sex. Histograms depict average ± SEM. Italicized bottom left text indicates statistically significant (*p<0.05) main effects and interactions. All statistical details can be found in Table 5.
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