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To the Editor, Keeping in mind our recent breakthrough in the field of biomedical effects of citrus flavanones, achieved by using an insufficiently exploited rat experimental model of old age (1,2), we consider it important to highlight the status of the antioxidative defense system in this animal model, as it is a crucial physiological definer. In general, aging represents a complex process characterized by the deterioration of overall health, slowing of the metabolism, and accumulation of numerous mutations (3). The United Nations World Population Aging Report in 2015 suggested that 12.5% of the entire human population is older than 60 years, while some demographic assessments of the World Bank predict it to reach 17% older than 65 years by 2050. Aging is associated with elevated incidences of chronic diseases, such as diabetes, hypertension, dyslipidemia, liver function disturbances, endocrine issues, osteoporosis, sarcopenia, and cancer (3,4). Changes in the antioxidant defense system (ADS), detoxification mechanisms, and cell reparation underlie the majority of the mentioned diseases (5). Namely, as a consequence of the decrease in ADS and cell reparation capacities during aging, the rate of oxidative damage increases. If reactive oxygen species (ROS) are not efficiently removed from the milieu, accumulation of oxidized and glycoxidized products can subsequently cause cellular senescence (6). It is well known that antioxidant enzymes such as superoxide dismutase (SOD) 1 and 2, catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR), as well as nonenzymatic glutathione (GSH), eliminate ROS such as superoxide anion (O 2− ) or hydrogen peroxide (H 2 O 2 ). As a consequence of the lack of their efficient removal, this can lead to damage of cellular proteins, lipids, and organelles. Oxidative metabolism in the liver causes the production of highly reactive ROS, whereby 90% of these molecules are generated in the mitochondria during the process of aerobic

The fulfillment of belonging needs underlies a variety of behaviors. In order to understand how social needs unmet during maturation shape everyday life, we examined social motivation and cognition in peripubertal rats, as a rodent model of adolescence, subjected to social isolation (SI) during early and early-to-mid adolescence. The behavioral correlates of social orientation (social space preference), sociability (preference for social over non-social novelty), and social novelty preference (SNP) were examined in group-housed (GH) and single-housed (SH) rats in a 3-chamber test. The response to social odors was examined to gain insights into the developmental role of social odors in motivated social behavior. Differentiation between appetitive (number of visits/approaches) and consummatory (exploratory time) aspects of motivated social behavior was done to determine which facet of social motivation characterizes maturation when social needs are met and which aspect dominates when social needs are unsatisfied. The SI-sensitive parvalbumin-expressing interneurons (PVI) in the hippocampus were examined using immunohistochemistry. The main findings are the following: (1) in GH rats, the preference for social space is not evident regardless of animals’ age, while sociability becomes apparent in mid-adolescence strictly through consummatory behavior, along with complete SNP (appetitive, consummatory); (2) SH promotes staying in a social chamber/space regardless of animals’ age and produces an appetitive preference for it only in early-adolescent animals; (3) SH promotes sociability (appetitive, consummatory) regardless of the animals’ age and prevents the SNP; (4) the preference for a social odor is displayed in all the groups through consummatory behavior, while appetitive behavior is evident only in SH rats; (5) the response to social odors does not commensurate directly to the response to conspecifics; (6) SH does not influence PVI in the hippocampus, except in the case of early-adolescence when a transient decrease in the dentate gyrus is observed. These results accentuate the developmental complexity of social motivation and cognition, and the power of SI in adolescence to infringe social maturation at different functional levels, promoting appetitive behavior toward peers overall but harming the interest for social novelty. The findings emphasize the importance of the fulfillment of basic social needs in the navigation through the social world.

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Changes in housing density, including individual housing, are commonly necessary in animal research. Obtaining reproducibility and translational validity in biomedical research requires an understanding of how animals adapt to changes in housing density. Existing literature mainly addresses acclimatization after transportation. We used a within-subject design to examine changes in behavior and weight gain of 4-mo-old male Wistar Han rats after reduction of their social group (RSG; due to removal of one rat from a cage containing 3 rats) and social isolation (SI; the removed rat) for the subsequent 2 wk. Changes in weight gain and in exploratory and center-avoidance behavior in an inescapable open arena (OA) were measured before (D0) and on days 7 and 14 (D7 and D14, respectively) after social change. The motor response to d-amphetamine (1.5 mg/kg), which stimulates behavioral arousal in response to novelty, was assessed at D14. Within-subject design revealed that RSG rats in OA had less locomotion at D7 but not more center-avoidance behavior and had returned to the D0 activity level at D14; SI rats in OA had consistently less locomotion and more center-avoidance behavior. Rearing behavior during OA exposure did not change in either group. However, SI rats showed more center-avoidance behavior in OA, greater weight gain, and less amphetamine-induced rearing at D14 as compared with RSG rats. These data indicate that after RSG, mature adult male rats require 2 wk to return to their baseline level of OA-related behavior, while after SI they gain weight and acquire maladaptive exploratory and center-avoidance behavior. The finding that SI produces maladaptive behavioral and physiologic alterations in adult male rats deserves attention because these changes could have confounding effects on research findings.