Sex differences in hippocampal long-term potentiation (LTP) and Pavlovian fear conditioning in rats: positive correlation between LTP and contextual learning

Abstract

Three experiments investigated sex differences in hippocampal long-term potentiation (LTP) and Pavlovian fear conditioning in rats. Experiment 1 revealed a robust sex difference in the magnitude of LTP induced at perforant path synapses in the dentate gyrus of pentobarbital-anesthetized rats. This sex difference in LTP was evident in rats of 35 and 60 days of age and was not the result of pre-LTP sex differences in perforant path synaptic transmission; 20-day-old rats did not show LTP. An analysis of field potentials evoked during LTP induction revealed a sex difference in the magnitude of N-methyl-D-aspartate (NMDA) receptor activation that was highly correlated with the magnitude of LTP. Experiment 2 showed that males condition more fear, measured as freezing, to the contextual conditional stimuli (CSs) of a conditioning chamber compared to their female counterparts. This sex difference in conditional freezing was apparent with both low and high unconditional stimulus (US, footshock) intensities. Experiment 3 revealed that the enhanced fear conditioning in males was specific to contextual CSs, and consisted of a more rapid rate of conditioning. Together, these experiments reveal a positive correlation between the magnitude of hippocampal LTP and a form of learning that depends on the hippocampus. Furthermore, they suggest a neural basis for sex differences in hippocampus-dependent learning tasks.

Scopolamine and Pavlovian Fear Conditioning in Rats Dose-Effect Analysis

“…All three tasks are disrupted by lesions of the hippocampus or NDMA receptor antagonism Anagnostaras et al 1999;Kim et al 1991;Morris et al 1986;Kawabe et al 1998) all three exhibit sexual dimorphism (Maren et al 1994b;Anagnostaras et al 1998;Williams and Meck 1991), and recent evidence indicates similar targeted mutations in mice disrupt these tasks (e.g., Lu et al 1997). The present report confirms that contextual fear conditioning, like the water (Hagan et al 1986) and radial (Levin et al 1990) mazes, is also sensitive to cholinergic disruption.…”

“…Conditioning was identical to Experiments 1 and 2, except for the following differences: 1) because male rats, which condition more rapidly than female rats (Maren et al 1994b), were used, three instead of five tone-shock pairings were given; and 2) the animals were divided into three groups: Immediate ( n ϭ 10)-animals received 10 mg/kg scopolamine, i.p., immediately after training and saline 24 hrs later; Delay ( n ϭ 9)-animals received saline immediately after training and 10 mg/kg scopolamine, i.p., 24 hrs after training; finally, saline Control ( n ϭ 10)-animals were given saline immediately after training and 24 hrs later. After training, great care was taken so that all animals received the injections within 2 min of the last shock.…”

Females do not Express Learned Helplessness like Males do

“…For example, females often respond actively to aversive stimulation, whereas males do so passively with freezing (Beatty and Beatty, 1970;Heinsbroek et al, 1991;Kirk and Blampied, 1985;Steenbergen et al, 1990). Females also express less conditional freezing than males during contextual fear conditioning (Gupta et al, 2001;Maren et al, 1994).…”

Sex differences in animal models of psychiatric disorders

“…In contextual fear conditioning, female rats show less learned freezing behaviour than male rats (Maren et al, 1994;Pryce et al, 1999). In cue fear conditioning, male rats again exhibit more conditioned fear than female rats, either when freezing or when ultrasonic vocalizations are used as a CR (Maren et al, 1994;Pryce et al, 1999;Kosten et al, 2005).It has been proposed that PTSD patients show reduced extinction of the fear induced by the traumatic experience (Milad et al, 2006;2008;Rauch et al, 2006). In animals, extinction can be assessed by exposing them repeatedly to the CS without the US and observe the reduction of the CR.…”