Exposure to Stressors Facilitates Long-Term Synaptic Potentiation in the Lateral Habenula

Abstract

The lateral habenula (LHb) is a small part of the epithalamus that projects to monoamine centers in the brain. Previously, neurotransmission onto the LHb was shown to be abnormally potentiated in animal models of depression. However, synaptic plasticity in this brain area and the effect of stressor exposure on synaptic plasticity of the LHb have not been investigated. Thus, we explored whether the LHb undergoes dynamic changes in synaptic efficacy or not. First, we observed that a moderate LTP occurs in a fraction of LHb neurons obtained from naive Sprague Dawley rats. Interestingly, a single exposure to acute stressors, such as inescapable foot shock or restraint plus tail shock (RTS), significantly enhances the magnitude of LTP in the LHb. We also observed an increased number of LHb neurons expressing phosphorylated cAMP response element-binding protein (pCREB) after exposure to stressors, which may contribute to determine the threshold for LTP induction. LTP induction in the LHb resulted in an additional increase in the number of pCREBexpressing neurons in stress-exposed animals but not in naive control animals. Together, we showed that LHb neurons have heterogeneous propensity for synaptic potentiation at rest; however, a single exposure to stressors greatly facilitates LTP induction in the LHb, suggesting that fundamental alterations in synaptic plasticity in the LHb may occur in animal models of depression or post-traumatic stress disorder.

Selectively Impaired Endocannabinoid-Dependent Long-Term Depression in the Lateral Habenula in an Animal Model of Depression

“…Surprisingly, a single exposure to restraint plus tail shock (RTS) selectively prevented LFS-LTD and mGluR-LTD induction while leaving a 13-Hz-induced LTD (MFS-LTD) intact. Together with our previous report (Park et al, 2017), our results show that the LHb exhibits bidirectional synaptic plasticity and that acute stress can greatly disrupt the balance between LTP and LTD in the LHb, shifting to further potentiation of LHb activity.…”

“…Prolonged MFS also induced LTD in the LHb. We recently showed that mild LTP also can occur in the LHb upon theta burst stimulation, although the magnitude of potentiation was smaller compared to that observed in other structures, including the hippocampus (Park et al, 2017). These findings implicate that the LHb exhibits bidirectional synaptic plasticity, although the efficacy for potentiation and that for depression do not seem to be equally balanced in the LHb.…”

“…To determine whether a single exposure to extreme stress alters the propensity to LTD in the LHb, we used the RTS stress paradigm (Chen et al, 2010;Kim et al, 1996;Park et al, 2017;Yang et al, 2004) and obtained acute brain slices 24 hr after the RTS exposure. Surprisingly, LHb neurons in the RTS group exhibited little depression upon LFS, if any (Figures 2A-2C; p > 0.1, compared to the baseline; p < 0.001, compared to the naive wild-type [WT] group).…”

“…We have recently shown that mild long-term potentiation (LTP) can be induced in a subpopulation of LHb neurons. Intriguingly, single exposure to acute stressors significantly enhanced the propensity to induce LTP (Park et al, 2017). However, it remains to be investigated whether the LHb exhibits long-term depression (LTD) and, if so, how stressful experiences may modulate LTD induction in the LHb.…”

Pathological ATPergic Signaling in Major Depression and Bipolar Disorder

“…A tight causal relationship of P2X7Rs with mood disorders is imperatively suggested by their involvement in neuroinflammation and the subsequent modulation/damage of neuronal circuits in mood-relevant areas of the brain. Functional changes in long-term synaptic potentiation (LTP) in the lateral habenula have been observed in rats exposed to inescapable stressors leading to learned helplessness (Li et al, 2011;Park et al, 2017). Similarly, in models of learned helplessness, the expression of synapse-related genes decreased, indicating the loss of synaptic structures.…”