Finally not only can ERs pair with different mGluRs
Finally, not only can ERs pair with different mGluRs in different y15 regions, but it is becoming increasingly clear that the same mGluRs can pair with distinct downstream signaling partners to have differential effects both within and across brain regions (Gross et al., 2016; Mannaioni et al., 2001; Poisik et al., 2003; Valenti et al., 2002). In other cases, mGluR signaling may result in the same outcome, but through distinct pathways (Benquet et al., 2002; Thandi et al., 2002). These nuances in mGluR signaling are an important consideration, as they likely contribute to the varied effects of estradiol on structural plasticity. The flexibility and diversity of ER/mGluR signaling outcomes are thus conferred at multiple levels. Learning the precise mechanism that determines which mGluR an ER pairs with, and the nature of downstream effects of that mGluR, will clarify our understanding of how estradiol modulates neural systems in specific and complex ways.
Future directions and conclusions This review has focused on estrogen regulation of female motivational behavior, as estrogens have not been found to directly affect brain regions associated with the reward pathway in male mammals (Becker, 2016; Cummings et al., 2014). Nevertheless, estrogens are known to play essential roles in avian physiology and behavior (Cornil et al., 2012), including through ER/mGluR signaling mechanisms (Seredynski et al., 2015). Moreover, ER/mGluR signaling has recently been described in the cerebellum of male mice (Hedges et al., 2018), a brain region known to affect an ever increasing variety of cognitive functions (Strick et al., 2009; Galliano and De Zeeuw, 2014). Thus, it would be premature to exclude the possibility of estrogen affecting motivated behaviors in male mammals. That said, androgen receptors (AR) are also palmitoylated by the same DHHC enzymes as estrogen receptors (Pedram et al., 2012), and thus may be trafficked to the surface membrane as well. Hence, current work is examining potential AR/mGluR signaling and its impact upon the reward circuitry in the brains of male mammals, similar to the effects of estrogens in females. Additionally, although the membrane-localized ER signaling described in this review has generally been studied in isolation from nuclear signaling, it is becoming clearer and clearer that integration of these mechanisms must be considered (Frick, 2015). Perhaps the distinct estradiol signaling mechanisms serve as a sort of coincidence detector in various systems, whereby the convergence of rapid and slow effects promotes a certain outcome. This can be seen in the case of sexual receptivity, as both the slower and more rapid effects of estradiol are required in the hypothalamus for the normal expression of sexual receptivity in females (Kow and Pfaff, 2004). Specifically, ERα/mGluR1a signaling leads to rapid internalization of μ-opioid receptors in the medial preoptic area (Dewing et al., 2007), followed by a slower, enduring increase in dendritic spine density in the arcuate nucleus (Christensen et al., 2011). Similarly, estradiol signaling through ERα/mGluR5 affects neuronal excitability in striatal cells on the order of seconds or minutes (Grove-Strawser et al., 2010), followed by slower effects on dendritic spine plasticity (Peterson et al., 2014). These differing time courses converge to enhance motivated behaviors in females, as seen in the findings from our lab and others on estradiol facilitation of cocaine-induced plasticity. Although nuclear estrogen receptors are not found in abundance in the NAc, nuclear ERs in other reward circuitry brain regions could contribute to the effects of estrogens on the development and maintenance of addiction. Thus, it stands to reason that nuclear estradiol signaling adds another layer to the processes discussed in this review, and careful work must be undertaken to dissect these signaling mechanisms. Doing so will help explain the special nature of the ER/mGluR relationship that allows estradiol to powerfully influence neuronal physiology, structure, and, ultimately, behavior.