A novel mechanism for how stress-induced anxiety affects function in the hippocampus, has been discovered by University of Alabama at Birmingham neurobiologist Lynn Dobrunz, Ph.D. Higher levels of neuropeptide Y ( NPY) are known to produce anxiety-relieving effects.

In contrast, NPY levels are reduced in people with post-traumatic stress disorder (PTSD) and other anxiety disorders.

Until now, the mechanism of how changing levels of neuropeptide Y alters circuit function to reduce or increase anxiety behavior has not been known. Besides describing a mechanism for that, the UAB researchers also have shown that the stress of exposing mice to a predator scent — a compound found in the feces of foxes — prevents the release of NPY, potentially enhancing anxiety.

The findings fill an important gap in knowledge between the molecular, circuit and behavioral effects of the brain-signaling molecule and could pave the way for new therapeutic targets to increase neuropeptide Y release in the appropriate brain pathway for patients with anxiety disorders.

Neuropeptide Y Pathways

The research focused on the CA1 area of the hippocampus. CA1 is involved in learning and memory, and distinct sets of neurons there are able to release NPY.

Two neural pathways activate CA1 — the Schaffer collateral, or SC, pathway and the temporoammonic, or TA, pathway.

While both pathways are involved in fear learning, the TA pathway has been shown to be particularly sensitive to stress. Using a novel, physiologically based assay, the researchers were able to send a train of electrical pulses through these pathways to stimulate the release of endogenous neuropeptide Y from three subtypes of neurons in CA1.

This release caused a change in plasticity — specifically, a suppression of short-term facilitation — of TA synapses onto excitatory neurons in the CA1. The endogenous release also changed plasticity of SC synapses, but this required activation of both the SC and TA pathways.

Importantly, the researchers found that stressing mice with predator scent — a mouse model of PTSD — impaired the release of endogenous neuropeptide Y in the TA pathway and altered the function of the TA synapses. This impairment of neuropeptide Y release, Dobrunz and colleagues say, contributes to circuit dysfunction in the CA1 area of the hippocampus in response to stress.

Chain Of Events

From this study and what others know about the hippocampus, the UAB results suggest the following train of events:

  1. The stress of smelling a predator scent impairs neuropeptide Y release.
  2. This reduction in neuropeptide Y release enhances short-term plasticity of TA synapses.
  3. The enhanced plasticity, in turn, boosts the strength of that pathway to drive more spiking of CA1 nerve cells.
  4. Increased spiking alters the hippocampal output, a changed output that may increase the consolidation of fear learning.

This novel assay could also be used to detect effects of endogenous neuropeptide Y release in other neurological and neuropsychiatric disorders where neuropeptide Y is implicated. These include epilepsy, depression and schizophrenia.

“Our study,” the authors wrote, “is the first demonstration of the impact of endogenously released neuropeptide Y on SC and TA short-term plasticity in response to stimulation with a physiologically derived spike train. While no in vitro experiment completely duplicates in vivo conditions, these experiments bring us one step closer to the physiological situation and advance our understanding of how temporally complex activity regulates neuropeptide Y release from neuropeptide Y-positive interneurons."

Post-traumatic stress disorder, a public health challenge, is marked by reactions to trauma or a life-threatening event that do not go away or even grow worse — reactions such as jumpiness, difficulty sleeping or upsetting memories. About 3.5 percent of the U.S. population has PTSD in a given year, and the rate for women is nearly three times higher than that for men, according to the U.S. Department of Veterans Affairs.

Qin Li, Aundrea F. Bartley and Lynn E. Dobrunz Endogenously Released Neuropeptide Y Suppresses Hippocampal Short-Term Facilitation and Is Impaired by Stress-Induced Anxiety Journal of Neuroscience 4 January 2017, 37 (1) 23-37; DOI: https://doi.org/10.1523/JNEUROSCI.2599-16.2017

Image: 3d structure of neuropeptide Y. Ref.: S.A.Monks et al. (1996). Solution structure of human neuropeptide Y.. J Biomol NMR, 8, 379-390

For future updates, subscribe via Newsletter here or Twitter