Brain circuit dynamics related to extremes in trait anxiety in mice

Anxiety disorders are among the most common psychiatric diseases and contribute to the development of other psychiatric conditions, such as major depression, leading to a high impairment of daily life quality. Although it is obvious that the physiological architecture of neuronal networks and its modifications are essential for the ability of the brain to process incoming information and to control highly organized behaviour, the mechanisms underlying anxiety disorders still remain poorly understood. We focused our attention on two brain structures, which are strongly involved in emotional responses of mammals, namely the hippocampus and the amygdala. Both structures belong to the limbic system and play fundamental roles in information processing. Recent findings indicate that alterations in neuronal network properties of these two brain areas critically contribute to the development of such disorders. To potentially uncover changes in neuronal network features associated with abnormal anxiety, we performed experiments in a well-established animal model of extremes in trait anxiety, the high vs. low anxiety-related behaviour (HAB/LAB) mice. HAB mice exposed to an enriched environment (HAB E.E.) and stressed LAB mice (LAB Str.) were also used in the present study. HAB E.E. animals showed decreased anxiety compared to standard HABs, whereas LAB Str. animals displayed an increase in anxiety levels compared to standard LABs. Anxiety levels were measured by means of the elevated plus maze. For our investigations, we employed classical electrophysiological techniques and high-speed voltage-sensitive dye imaging (VSDI) in acute hippocampal (dorsal & ventral) and amygdalar brain slices. Field potential recordings revealed that HAB animals exhibit weaker long-term potentiation at CA3-CA1 synapses (CA1 LTP) in the dorsal hippocampus and an increased LTP in the ventral hippocampus compared to LAB and control CD1 mice. These observations could support the idea of an exacerbated activation of the “emotional” (ventral) hippocampus concomitantly with a decreased activity in the “cognitive” (dorsal) hippocampus, findings that have also been made in patients suffering from anxiety disorders. To examine whether neuronal activity propagation through the amygdala differs between HAB, HAB E.E. , LAB and LAB Str. mice, we used a quantitative VSDI approach. Our results demonstrate that HAB animals exhibit stronger neuronal activity propagation through the amygdala compared to LAB mice. This indicates that differences in anxiety levels may correlate with the effectiveness of neuronal activity flow through the amygdalar network. Our study also provides strong evidence that environmentally induced shifts in trait anxiety are associated with changes in intrinsic amygdalar network properties. To summarize, HAB animals showed increased “excitability” in the ventral hippocampus and in the amygdalar network, both structures known to be involved in the control of emotional states and in the stress response in mammals. In addition, the differences in amygdalar network activity were rescued by environmental conditions (enriched environment). Dysregulation of these structures could lead to the “pathologic anxiety-like” behaviour, which can be observed in HAB animals.