Hippocampal mossy fiber leu-enkephalin immunoreactivity in female rats is significantly altered following both acute and chronic stress

Abstract

Research indicates that responses to stress are sexually dimorphic, particularly in regard to learning and memory processes: while males display impaired cognitive performance and hippocampal CA3 pyramidal cell dendritic remodeling following chronic stress, females exhibit enhanced performance and no remodeling. Leu-enkephalin, an endogenous opioid peptide found in the hippocampal mossy fiber pathway, plays a critical role in mediating synaptic plasticity at the mossy fiber-CA3 pyramidal cell synapse. Estrogen is known to influence the expression of leu-enkephalin in the mossy fibers of females, with leu-enkephalin levels being highest at proestrus and estrus, when estrogen levels are elevated. Since stress is also known to alter the expression of leu-enkephalin in various brain regions, this study was designed to determine whether acute or chronic stress had an effect on mossy fiber leu-enkephalin levels in females or males, through the application of correlated quantitative light and electron microscopic immunocytochemistry. Both acute and chronic stress eliminated the estrogen-dependence of leu-enkephalin levels across the estrous cycle in females, but had no effect on male levels. However, following acute stress leu-enkephalin levels in females were consistently lowered to values comparable to the lowest control values, while following chronic stress they were consistently elevated to values comparable to the highest control values. Ultrastructural changes in leu-enkephalin labeled dense core vesicles paralleled light microscopic observations, with acute stress inducing a decrease in leu-enkephalin labeled dense core vesicles, and chronic stress inducing an increase in leu-enkephalin labeled dense-core vesicles in females. These findings suggest that alterations in leu-enkephalin levels following stress could play an important role in the sex-specific responses that females display in learning processes, including those important in addiction.

Opioid Receptor-Dependent Sex Differences in Synaptic Plasticity in the Hippocampal Mossy Fiber Pathway of the Adult Rat

“…D, The MF synapse is illustrated schematically for a female on proestrous morning. The levels of enkephalins are higher in proestrous female rats compared with male rats (Pierce et al, 2014). D1, Basal transmission in proestrous females.…”

“…However, an effect of postsynaptic MORs on basal transmission would require enkephalin release, and it is generally assumed that neuropeptide release requires high-frequency stimulation (Cheng and Pomeranz, 1979;Bartfai et al, 1988;Thureson-Klein and Klein, 1990). Notably, extremely high frequencies of stimulation may not be required to release enkephalins in proestrous females because MF enkephalin levels increase at that time (Torres-Reveron et al, 2008;Pierce et al, 2014). In addition, dense core vesicles containing neuropeptides move closer to the plasma membrane in response to 17␤-estradiol (Tabatadze et al, 2013) Diestrous-1 females showed a smaller effect of naloxone and CTOP on basal transmission.…”

“…In addition, dense core vesicles containing neuropeptides move closer to the plasma membrane in response to 17␤-estradiol (Tabatadze et al, 2013) Diestrous-1 females showed a smaller effect of naloxone and CTOP on basal transmission. One would not expect any effect however, because MF enkephalin expression on diestrus-1 is similar to males (Pierce et al, 2014). Moreover, serum levels of 17␤-estradiol are low in diestrous-1 females (Freeman, 1984).…”

“…Indeed, varied affinities of MORs have been reported and MFs preferentially express one subtype (MOR1D; Abbadie et al, 2000). Affinity may play an even greater role in proestrous females because MORs change affinity in response to estrogen (Piva et al, 1995).…”

“…Moreover, there are sex differences and gonadal steroid regulation of opioid peptide levels and MOR/DOR trafficking (TorresReveron et al, 2008(TorresReveron et al, , 2009aWilliams et al, 2011b;Burstein et al, 2013;Milner et al, 2013;Pierce et al, 2014). Finally, male LTP is facilitated by MORs on MF terminals (Martin, 1983;Derrick et al, 1991Derrick et al, , 1992Jin and Chavkin, 1999;Jamot et al, 2003).…”