Figure 1.

Cognitive impairment caused by short-term obesogenic diet is reversed by central pregnenolone administration.

(A) Schematic illustration of Barnes maze test (BMT) and experimental timeline. The white circle and the rectangle represent the scape hole and scape chamber location, respectively. The position of the scape chamber remained constant on each trial. On the test day, the scape hole was closed and the chamber removed.

(B) Schematic illustration of the novel object recognition test (NORT) and experimental chronology.

(C–F) Recorded parameters to assess BMT performance in mice fed with either chow or western diet for 4 days (4d-WD) during the test phase: (C) latency to target hole, (D) time spent in target quadrant, (E) total distance traveled, and (F) representative traces of mouse movement trajectories (n = 11/diet).

(G–J) Recorded parameters to assess NORT performance in mice fed with either chow or 4d-WD during the test phase: (G) discrimination index (time exploring novel object − time exploring familiar object)/(time exploring novel object + time exploring familiar object), (H) exploration time (time exploring novel object + time exploring familiar object), (I) total distance traveled, and (J) representative traces of mouse movement trajectories (n = 9–10/diet).

(K–N) Hippocampal long-term potentiation (LTP) study in mice fed with chow or 4d-WD. (K) Schematic illustration of the experimental strategy. The Schaffer collateral pathway (SC, red) was stimulated (Stim), and field potentials were recorded (Rec) in the CA1 region of the hippocampus. LTP was induced by theta-burst stimulation (TBS). DG, dentate gyrus; CA, cornu ammonis.

(L) Representative traces of individual recordings showing baseline fEPSPs before (black traces) and after (red traces) LTP induction.

(M) Time course of fEPSP recordings demonstrating robust changes in fEPSP slope in chow-fed animals after TBS (arrow) (n = 5 recordings from 4 animals). In 4d-WD animals, LTP induction was markedly impaired (n = 7 recordings from 4 animals).

(N) Quantification of fEPSP slope change over the last 45 min of recording period shown in (M).

(O–Q) Quantification of pregnenolone concentration in the (O) perirhinal cortex, (P) hippocampus, and (Q) arcuate-enriched mediobasal hypothalamus in mice fed with either chow or 4d-WD (n = 7–8/diet).

(R) Schematic illustration of central acute delivery of pregnenolone and subsequent NORT. Red arrow shows injection phase.

(S) Discrimination index during the test phase of NORT in mice fed with either chow or 4d-WD treated with vehicle (Veh) or pregnenolone (Preg) (n = 6–8/group).

All studies were performed on male mice at 8–9 weeks of age. Dots in panels represent individual samples. Data are presented as mean ± SEM. ^∗p < 0.05.