Connecting the Dots: Potential Interactions Between Sex Hormones and the Circadian System During Memory Consolidation.

Both the circadian clock and sex hormone signaling can strongly influence brain function, yet little is known about how these 2 powerful modulatory systems might interact during complex neural processes like memory consolidation. Individually, the molecular components and action of each of these systems have been fairly well-characterized, but there is a fundamental lack of information about how these systems cooperate. In the circadian system, clock genes function as timekeeping molecules that convey time-of-day information on a well-stereotyped cycle that is governed by the suprachiasmatic nucleus. Keeping time is particularly important to synchronize various physiological processes across the brain and body, including those that regulate memory consolidation. Similarly, sex hormones are powerful modulators of memory, with androgens, estrogens, and progestins, all influencing memory consolidation within memory-relevant brain regions like the hippocampus. Despite clear evidence that each system can influence memory individually, exactly how the circadian and hormonal systems might interact to impact memory consolidation remains unclear. Research investigating either sex hormone action or circadian gene function within memory-relevant brain regions has unveiled several notable places in which the two systems could interact to control memory. Here, we bring attention to known interactions between the circadian clock and sex hormone signaling. We then review sex hormone-mediated control of memory consolidation, highlighting potential nodes through which the circadian system might interact during memory formation. We suggest that the bidirectional relationship between these two systems is essential for proper control of memory formation based on an animal's hormonal and circadian state.

The clock gene Per1 may exert diurnal control over hippocampal memory consolidation.

The circadian system influences many different biological processes, including memory performance. While the suprachiasmatic nucleus (SCN) functions as the brain's central pacemaker, downstream "satellite clocks" may also regulate local functions based on the time of day. Within the dorsal hippocampus (DH), for example, local molecular oscillations may contribute to time-of-day effects on memory. Here, we used the hippocampus-dependent Object Location Memory task to determine how memory is regulated across the day/night cycle in mice. First, we systematically determined which phase of memory (acquisition, consolidation, or retrieval) is modulated across the 24 h day. We found that mice show better long-term memory performance during the day than at night, an effect that was specifically attributed to diurnal changes in memory consolidation, as neither memory acquisition nor memory retrieval fluctuated across the day/night cycle. Using RNA-sequencing we identified the circadian clock gene Period1 (Per1) as a key mechanism capable of supporting this diurnal fluctuation in memory consolidation, as learning-induced Per1 oscillates in tandem with memory performance in the hippocampus. We then show that local knockdown of Per1 within the DH impairs spatial memory without affecting either the circadian rhythm or sleep behavior. Thus, Per1 may independently function within the DH to regulate memory in addition to its known role in regulating the circadian system within the SCN. Per1 may therefore exert local diurnal control over memory consolidation within the DH.

Dopamine D1 receptor activation drives plasticity in the songbird auditory pallium.

Vocal learning species must form and extensively hone associations between sounds and social contingencies. In songbirds, dopamine signaling guides song motor-production, variability, and motivation, but it is unclear how dopamine regulates fundamental auditory associations for learning new sounds. We hypothesized that dopamine regulates learning in the auditory pallium, in part by interacting with local neuroestradiol signaling. Here, we show that zebra finch auditory neurons frequently coexpress D1 receptor (D1R) protein, neuroestradiol-synthase, GABA, and parvalbumin. Auditory classical conditioning increased neuroplasticity gene induction in D1R-positive neurons. In vitro, D1R pharmacological activation reduced the amplitude of GABAergic and glutamatergic currents and increased the latter's frequency. In vivo, D1R activation reduced the firing of putative interneurons, increased the firing of putative excitatory neurons, and made both neuronal types unable to adapt to novel stimuli. Together, these findings support the hypothesis that dopamine acting via D1Rs modulates auditory association in the songbird sensory pallium.SIGNIFICANCE STATEMENTOur key finding is that auditory forebrain D1 receptors modulate auditory plasticity, in support of the hypothesis that dopamine modulates the formation of associations between sounds and outcomes. Recent work in songbirds has identified roles for dopamine in driving reinforcement learning and motor variability in song production. This leaves open whether dopamine shapes the initial events that are critical for learning vocalizations, e.g., auditory learning. Our study begins to address this question in the songbird caudomedial nidopallium (NCM), an analogue of the mammalian secondary auditory cortex. Our findings indicate that dopamine receptors are important modulators of excitatory/inhibitory balance and sound association learning mechanisms in the NCM, a system that could be a fundamental feature of vertebrate ascending auditory pathways.