CRK and NCK adaptors may functionally overlap in zebrafish neurodevelopment, as indicated by common binding partners and overlapping expression patterns.

CRK adaptor proteins are important for signal transduction mechanisms driving cell proliferation and positioning during vertebrate central nervous system development. Zebrafish lacking both CRK family members exhibit small, disorganized retinas with 50% penetrance. The goal of this study was to determine whether another adaptor protein might functionally compensate for the loss of CRK adaptors. Expression patterns in developing zebrafish, and bioinformatic analyses of the motifs recognized by their SH2 and SH3 domains, suggest NCK adaptors are well-positioned to compensate for loss of CRK adaptors. In support of this hypothesis, proteomic analyses found CRK and NCK adaptors share overlapping interacting partners including known regulators of cell adhesion and migration, suggesting their functional intersection in neurodevelopment.

Cyclic estrogen and progesterone during instrumental acquisition contributes to habit formation in female rats.

Habit formation is thought to involve two parallel processes that are mediated by distinct neural substates: one that suppresses goal-directed behavior, and one that facilitates stimulus-response (S-R) learning, which underscores habitual behavior. In previous studies we showed that habitual responding emerges early during instrumental training in gonadally-intact female, compared to male, rats. The present study aimed to determine the role of ovarian hormones during instrumental acquisition in the transition from goal-directed to habitual behavior in female rats. Ovariectomized (OVX) female rats were given subcutaneous silastic capsules that released low levels of 17-ß estradiol (E2) to maintain estrogen receptor availability. Rats were assigned to one of three hormone treatment conditions: no additional hormone replacement (Control group), replacement with high E2 (High E2 group), or replacement with high E2 followed by progesterone (High E2 + P4 group). Hormone replacement occurred twice during acquisition to mimic natural hormone fluctuations. At test, the Control and High E2 groups demonstrated responding that was sensitive to devaluation by lithium chloride-induced illness, indicating goal-directed behavior. In contrast, the High E2 + P4 group exhibited a pattern of devaluation-insensitive, habitual responding, that suggested the suppression of goal-directed processes. In a follow-up experiment, similar procedures were conducted, however during acquisition, OVX rats were given cyclic high E2 plus medroxy-progesterone (MPA), a form of progesterone that does not metabolize to neuroactive metabolites. In this group, goal-directed behavior was observed. These data indicate that habit formation is not facilitated in low estrogen states, nor in the presence of cyclic high E2. However, cyclic high E2, together with progesterone during acquisition, appears to facilitate the early emergence of habitual responding. Furthermore, these data suggest that a neuroactive progesterone metabolite, like allopregnanolone, in combination with high cyclic E2, supports this phenomenon.