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.