Examining Sex Differences in Hippocampal Theta Activity in Relation to Anxiety-Like Behaviours in Rats

Abstract

Hippocampal theta activity is an oscillatory, highly rhythmic (4-14 Hz) activity pattern generated by the hippocampal formation of mammals. Theta activity has been linked to anxiety states in rodent, based on a number of studies showing that anxiety-reducing pharmacological agents (anxiolytics) consistently decrease the frequency of theta activity in rats, leading to the influential “theta suppression model of anxiolysis.” To this date, very few studies have systemically compared anxiety-related defensive behaviour and hippocampal theta activity in males and females. The primary objectives of this thesis were to examine a possible association of theta frequency and behavioural levels of “anxiety” in individual rats, and to examine potential sex differences in anxiety, theta activity, and the anxiety-theta association. Female and male rats were tested on the elevated plus maze (EPM), a common paradigm to assess anxiety in rodents. Interestingly, the findings reveal that females exhibited higher amounts of open arm activity (number of open arm entries and open arm time) compared to males, indicative of reduced “anxiety” in females. Following the behavioral assessment, the same rats were anesthetized using urethane and underwent electrophysiological procedures to characterize hippocampal theta frequencies activity. Theta activity was recorded in the CA1 field of the hippocampus and was elicited by electrical stimulation of the brainstem reticular formation (consisting of 5-s trains of 0.1 ms duration pulses delivered at 100 Hz). Systemic administration of the clinically used anxiolytic drug buspirone, which acts as a partial agonist at 5-HT1A receptors, was shown to decrease the frequency of theta activity, a finding that is in agreement with prior work. These experiments showed that there was no sex difference in theta frequency, and that theta frequency in individual rats did not correlate with behavioral measures of anxiety in the EPM. Together, the results of this work show that theta frequency does not predict levels of anxiety-like behavior in the EPM and challenge the predictive validity of hippocampal theta frequency as an index of anxiety levels.