Janet L. Menard

Repeated exposure to stress across the childhood-adolescent period alters rats' anxiety- and depression-like behaviors in adulthood: The importance of stressor type and gender.

This research tests the hypothesis that specific forms of adversity in early life map onto behavioral signs analogous to depression versus anxiety in later life. Male and female rats were exposed to either severe sporadic stress or chronic mild stress during the childhood-adolescent period, and their behavior was tested in adulthood. Males in the severe sporadic stress group showed exaggerated anxiety-related behaviors, as indicated by increases in shock-probe burying and escape-like responses (jumps) from the open arms of the elevated plus-maze. Females exposed to severe sporadic stress displayed no change in burying behavior but did display increases in escape behavior. These same females also exhibited behaviors analogous to depression that manifested as decreased sucrose consumption. The chronic mild stress regime produced effects only in females, including reduced burying, decreased sucrose consumption, and an exaggerated corticosterone response to cold-water immersion stress. Findings reiterate the importance of early life experience to the development of adult psychopathologies and emphasize the need to consider both the type of early experience and gender differences in these analyses.

Variations of maternal care alter offspring levels of behavioural defensiveness in adulthood: Evidence for a threshold model

Natural variations of maternal care in the rat influence the development of neuronal systems that regulate defensive responses to threat. Thus, as adults, rats that received higher levels of maternal licking/grooming (LG) in infancy display dramatic reductions in burying in the shock-probe test, relative to offspring of low LG mothers. We sought to replicate that finding and determine whether maternal care similarly influences offspring responses to social threat, using the resident-intruder test. We also examined whether maternal LG influences offspring behaviour along a continuum by comparing defensive responses of offspring of mid LG mothers to those of offspring of high LG and low LG mothers. A final goal was to assess whether the reductions in adult offspring reactivity to threat that typically follow corticosterone (CORT) administration to dams across lactation are mediated through CORT-induced changes in maternal care. Adult offspring of high LG mothers spent less time burying the shock-probe, relative to offspring of mid and low LG mothers, whereas offspring of CORT-treated mothers did not differ from any group. Similarly, offspring of high LG (but not CORT-treated) mothers displayed fewer defensive responses in the resident-intruder test. Thus, only natural variations of maternal care were associated with individual differences in offspring reactivity to threat. Furthermore, because offspring of mid and low LG mothers displayed equivalent levels of defensive responding in both tests, it appears that a critical threshold of maternal LG is necessary to alter the developmental trajectory of neural systems mediating defensive behaviours.

Intra-septal infusions of excitatory amino acid receptor antagonists have differential effects in two animal models of anxiety.

Ablation or pharmacological inhibition of the septum produces anxiolytic-like effects in two animal models of anxiety: the elevated plus-maze and the shock-probe burying tests. Overall, these results suggest that the septum normally plays an excitatory role in the control of anxiety-related behaviors. The purpose of the present study was to examine this hypothesis in more detail, by testing the effects of intra-septal infusions of excitatory amino acid (EAA) receptor antagonists on rats’ behavior in the shock-probe and plus-maze tests. We found that intra-septal infusions of the non-NMDA (N-methyl-d-aspartic acid) receptor antagonist CNQX (5 μg) suppressed open-arm avoidance in the plus-maze test, and reduced burying behavior in the shock-probe test, without affecting rats’ normal avoidance of the shock-probe. In contrast, intra-septal infusions of the NMDA receptor antagonist AP-5 (5 μg) inhibited both shock-probe avoidance and burying behavior, without affecting rats’ open-arm avoidance. These dissociations suggest that different EAA receptor types within the septum exert complex but distinct control of different anxiety-related behaviors.

Post-weaning social isolation increases activity in a novel environment but decreases defensive burying and subchronic MK-801 enhances the activity but not the burying effect in rats

Subchronic treatment with a non-competitive glutamate NMDA-receptor antagonist [e.g., MK-801 or phencyclidine] or social isolation (SI) from weaning (age 21 days) to adulthood (age 56 days) produce deficits similar to some of the positive and negative symptoms of schizophrenia. Few studies have evaluated the effects of these treatments on emotional behavior. We hypothesized that subchronic MK-801, post-weaning SI or the two in combination would alter activity in a novel environment, anxiety-like behaviors in the elevated plus-maze, coping responses in the defensive burying paradigm and social behavior. In experiment 1, SI rats (n=17) showed increased locomotor activity when exposed to a novel environment, no change in plus-maze behavior and decreased defensive burying when compared to group housed rats (n=16). Subchronic MK-801 enhanced the increase in activity but not the decrease in burying in SI rats. Experiment 2 evaluated the effects on social behavior of post-weaning SI. The locomotor and burying results of experiment 1 were replicated and SI rats (n=9) were found to decrease orientation towards a novel conspecific social target when compared to group housed rats (n=8). The behavioral abnormalities of SI rats may be a manifestation of GABAergic dysfunction that has recently become evident in schizophrenia.

The Septum and Anxiety

The septum has been implicated in the mediation of a number of behavioral processes (see this volume), including learning and memory (e.g., Parent and Gold 1997), aggression and defense (e.g., Albert and Chew 1980), behavioral inhibition (e.g., Gray 1982), reward (e.g., Olds and Milner 1954), and anxiety (Gray 1982, 1991; Treit and Pesold 1990). Although all of these postulated functions of the septum are conceptually intertwined to some degree, this chapter will focus on the putative role of the septum in anxiety. The theoretical impetus for this research comes from J.A. Gray’s important work (1982) on the neuropsychology of anxiety, and the empirical foundation comes from work using pharmacologically validated animal models of anxiety (Treit 1985a). The confluence of these two streams defines the main body of this chapter.

The lateral septum as a regulator of hippocampal theta oscillations and defensive behavior in rats

Hippocampal theta oscillations are linked to various processes, including locomotion, learning and memory, and defense and affect. The lateral septum (LS) has been implicated in the generation of the hippocampal theta rhythm, but its precise role in this process is not well understood. Here, we investigated the effects of direct pharmacological inhibition or disinhibition of the dorsal LS (dLS) on the frequency of hippocampal theta activity elicited by stimulation of the reticular formation in urethane-anesthetized rats. We found that bilateral infusions of the GABAA receptor agonist muscimol into the dLS significantly increased theta frequency. Strikingly, intra-dLS infusions of the GABAA receptor antagonist GABAzine largely abolished reticularly elicited theta activity. We also locally injected these same compounds into the medial septum (MS) to test for neuroanatomical specificity. In contrast to the effects seen in the dLS, intra-MS infusions of muscimol had no effect on theta frequency, whereas intra-MS infusions of GABAzine increased theta frequency. Given the hypothesized role of hippocampal theta in behavioral defense, we also examined the effects of intra-dLS application of muscimol in two models of anxiety, the elevated plus maze and the novelty-induced suppression of feeding paradigm; both tests revealed clear, anxiolytic-like effects following muscimol infusions. The fact that dLS-muscimol increased theta frequency while also reducing anxiety-like behaviors challenges the influential theta suppression model of anxiolysis, which predicts a slowing of theta with anxiolytic compounds. More importantly, the experiments reveal a novel role of the LS, especially its dorsal aspects, as an important gating mechanism for the expression of theta oscillations in the rodent hippocampus.

Lesions of the dorsal lateral septum do not affect neophagia in the novelty induced suppression of feeding paradigm but reduce defensive behaviours in the elevated plus maze and shock probe burying tests.

Past studies have shown that the lateral septum is involved in anxiety. Here, we tested whether the dorsal lateral septum contributes to neophagia by using the novelty induced suppression of feeding (NISF) paradigm. We found that while lesions of the dorsal lateral septum did not affect home or novel cage responding in the NISF test, they did decrease open arm avoidance in the elevated plus maze and burying in the shock probe burying test. Our results suggest that the dorsal lateral septum does not regulate neophagia in the NISF, but further experiments are needed to determine if the same is true for the intermediate and ventral lateral septum.

Electrical stimulation of dorsal, but not ventral hippocampus reduces behavioral defense in the elevated plus maze and shock-probe burying test in rats.

Recent evidence indicates that the hippocampus contributes to the control of defensive behaviors in rodents. Here, electrical stimulation (1s, 60 Hz) of the rat dorsal hippocampus inhibited defense in the elevated plus maze (increased open arm exploration) and shock-probe burying test (reduced burying duration), while ventral hippocampal stimulation had no effects. Thus, the dorsal hippocampus may play an important role in modulating a range of defensive strategies.

Behavioral anxiolysis without reduction of hippocampal theta frequency after histamine application in the lateral septum of rats.

Hippocampal theta activity is linked to various processes, including locomotion, learning and memory, and defense and affect (i.e., fear and anxiety). Interestingly, all classes of clinically effective anxiolytics, as well as experimental compounds that decrease anxiety in pre‐clinical animal models of anxiety, reduce the frequency of hippocampal theta activity elicited by stimulation of the reticular formation in freely behaving or anesthetized animals. In the present experiments, we found that bilateral histamine infusions (0.5 µg/hemisphere) into the lateral septum (LS) of rats decreased anxiety‐like responses in two models of anxiety, the elevated plus maze and novelty‐induced suppression of feeding test. Surprisingly, these same infusions significantly increased hippocampal theta frequency elicited by reticular stimulation in urethane‐anesthetized rats. In contrast to these findings, additional experiments showed that the clinically effective anxiolytic buspirone (40 mg/kg, i.p.) reduced theta frequency, confirming previous observations. Taken together, the dissociation of behavioral anxiolysis and theta frequency reduction noted here suggest that hippocampal theta frequency is not a direct index of anxiety levels in rodents. Further, the mechanisms underlying the behavioral and physiological effects elicited by histamine in the LS require further study.