Taming the Fear Response

Disorders arising from trauma and stress, such as post-traumatic stress disorder (PTSD), are a major cause of morbidity and mortality, and they exact a huge economic toll on our society. Hence, a major effort is underway to find new treatments for these diseases. A clue to possible novel therapeutic targets comes from the observation that cholinergic neurons from the basal forebrain suppress the conditioned fear response through modulation of synaptic transmission in the prefrontal cortex (PFC). The PFC, a center of higher-order cognitive function, coordinates signaling from both the ventral hippocampus (vHIPP) and the basolateral amygdala (BLA), both of which play a major role in the response to fear and trauma. These considerations led Vanderbilt Basic Sciences investigators Jeff Conn and Craig Lindsley to further explore the importance of cholinergic neurons in regulating fear responses in the PFC.

The researchers first showed that the generalized cholinergic agonist oxotremorine-M (Oxo-M) induces long-term depression (LTD) of synaptic transmission in PFC coronal slices from mouse brain. Using optogenetic techniques, they were then able to confirm that this LTD effect specifically targeted neuronal signals from the vHIPP and the BLA. Furthermore, using an antagonist and a positive allosteric modulator that selectively target the M₁ muscarinic acetylcholine receptor, they demonstrated that this receptor subtype was necessary for the LTD response. Together, these data indicated that cholinergic neuronal pathways to the PFC excite M₁ receptors, leading to LTD of synaptic responses to signals coming from the vHIPP and BLA.

To see if the effect they had observed plays a role in fear conditioning in vivo, the researchers employed a 5-day protocol through which they first conditioned mice to associate a mild foot shock with both a sound (cue) and a specific environment (context). They then subsequently exposed them individually to the cue and then the context in the absence of the shock, leading to a reduction (extinction) of the fear response. They found that treatment of the mice with an M₁ antagonist interfered with extinction to the context but not the cue. They further evaluated the role of M₁ in the fear response using a mouse model of PTSD in which mice were first exposed to random foot shocks prior to brief conditioning to additional shocks within a defined context. Subsequent exposure to the context without the shocks led to reduction in the fear response that was augmented in mice treated with an M₁ positive allosteric modulator.

These findings suggest that M₁-dependent cholinergic signaling plays a role in the suppression of fear responses under high stress conditions. Thus, therapy targeting M₁ may be valuable in the prevention and/or therapy of PTSD. These studies were only possible because of much prior work in the Conn and Lindsley laboratories that led to the discovery of multiple isoform-selective agonists, antagonists, and allosteric modulators of the cholinergic receptors. We look forward to further studies of the therapeutic potential of these important tool compounds. The work is published in the journal Biological Psychiatry.