Sexual dimorphism in learning and memory in middle aged McGill-R-Thy1-APP transgenic rat model of brain amyloidosis

N. COLETTIS; M. V. OBERHOLZER; M. HABIF; M. CERCATO; D. SALAS; J. RUSSO; C. CUELLO; D. JERUSALINSKY

Belem

Congreso; 3rd FALAN Congress; 2022

Internation Brain Research Organization

McGill‐R‐Thy1‐APP transgenic (Tg) Wistar rat model of Alzheimer´s disease bears a transgene ofhuman amyloid precursor protein‐751 (APP751) with both Swedish and Indiana mutations (Leonet al., 2010). As sexual dimorphism emerged in 12‐13‐month‐old wild‐type (Wt) Wistar rats insome memory tasks (Oberholzer, FALAN 2022), we comparatively assessed learning andmemory in 12‐13‐month‐old heterozygous (+/−)Tg male and female rats and their Wtlittermates.Open field task (OF) was used to assess spontaneous (horizontal and vertical) exploration,habituation to the environment and anxiety‐like behavior.Novel Object Recognition task (NOR) ‐mainly depending on cerebral cortex‐ assesses rat’scapacity to discriminate new from familiar objects. Training session: two similar objects (A) and(A’) were presented. Test‐sessions: 1h later, the familiar (A) and a novel object (B) werepresented to assess short‐term memory (STM); 24h later, (A) and a different object (C) werepresented to assess long‐term memory (LTM).Novel Object Location task (NOL) was used to investigate spatial reference memory –mainlydepending on hippocampus‐. 24 h after the last NOR Test session, same two familiar objects (A)and (A´) were presented, though one at a different location (A´).Inhibitory avoidance step‐through task (IA) involves aversive and spatial components ‐entailingthe hippocampus and the amygdala‐, and allows to evaluate associative learning and memory.Training (Tr): the rat was left in an illuminated compartment connected to a dark one; a mildfoot‐shock was applied when it entered the dark chamber; latency to get into the latter wasrecorded. Test session: the same procedure was performed with no foot‐shock 24 h later (Te) toassess LTM.OF: Exploratory parameters were significantly lower for all groups in the second session. Wtfemales evidenced higher vertical activity (rearings) than Wt males in both sessions, while forTg+/‐ females the number of rearings was significantly higher compared to Tg+/‐ males only inthe second session.NOR: Rats spent significantly longer time exploring (B) than (A) in all groups; discriminating thenovel from the familiar object (STM). Wt rats spent more time exploring (C) than (A), denotingLTM formation, while Tg+/‐ rats spent similar time exploring both objects, regardless of sex.However, 4‐5‐month‐old Tg+/‐ females were able to form this LTM while males did not.NOL: Only Wt females explored more time (A’), being able to discriminate the new location, thatimplies remembering the previous configuration. Tg+/‐ females, and both Wt and Tg+/‐ malesneither remembered the previous configuration nor discriminated the new position.IA: during Te latencies were significantly higher for both Wt and Tg+/‐ females, and for Wt males,indicating that a LTM was formed, though not for Tg+/‐ males, suggesting that LTM was notestablished/expressed.Our results emphasize the relevance of considering sex as a variable when interpreting cognitivefunctions data, and, particularly, when transgenic or other pathological rat models arecompared with wild type animals at middle age or older.