Dopamine receptor 1 neurons in the dorsal striatum regulate food anticipatory circadian activity rhythms in mice.

Daily rhythms of food anticipatory activity (FAA) are regulated independently of the suprachiasmatic nucleus, which mediates entrainment of rhythms to light, but the neural circuits that establish FAA remain elusive. In this study, we show that mice lacking the dopamine D1 receptor (D1R KO mice) manifest greatly reduced FAA, whereas mice lacking the dopamine D2 receptor have normal FAA. To determine where dopamine exerts its effect, we limited expression of dopamine signaling to the dorsal striatum of dopamine-deficient mice; these mice developed FAA. Within the dorsal striatum, the daily rhythm of clock gene period2 expression was markedly suppressed in D1R KO mice. Pharmacological activation of D1R at the same time daily was sufficient to establish anticipatory activity in wild-type mice. These results demonstrate that dopamine signaling to D1R-expressing neurons in the dorsal striatum plays an important role in manifestation of FAA, possibly by synchronizing circadian oscillators that modulate motivational processes and behavioral output.

Delta opioid receptors presynaptically regulate cutaneous mechanosensory neuron input to the spinal cord dorsal horn.

Cutaneous mechanosensory neurons detect mechanical stimuli that generate touch and pain sensation. Although opioids are generally associated only with the control of pain, here we report that the opioid system in fact broadly regulates cutaneous mechanosensation, including touch. This function is predominantly subserved by the delta opioid receptor (DOR), which is expressed by myelinated mechanoreceptors that form Meissner corpuscles, Merkel cell-neurite complexes, and circumferential hair follicle endings. These afferents also include a small population of CGRP-expressing myelinated nociceptors that we now identify as the somatosensory neurons that coexpress mu and delta opioid receptors. We further demonstrate that DOR activation at the central terminals of myelinated mechanoreceptors depresses synaptic input to the spinal dorsal horn, via the inhibition of voltage-gated calcium channels. Collectively our results uncover a molecular mechanism by which opioids modulate cutaneous mechanosensation and provide a rationale for targeting DOR to alleviate injury-induced mechanical hypersensitivity.

Food anticipatory activity behavior of mice across a wide range of circadian and non-circadian intervals.

When rodents are fed in a limited amount during the daytime, they rapidly redistribute some of their nocturnal activity to the time preceding the delivery of food. In rats, anticipation of a daily meal has been interpreted as a circadian rhythm controlled by a food-entrained oscillator (FEO) with circadian limits to entrainment. Lesion experiments place this FEO outside of the light-entrainable circadian pacemaker in the suprachiasmatic nucleus. Mice also anticipate a fixed daily meal, but circadian limits to entrainment and anticipation of more than 2 daily meals, have not been assessed. We used a video-based behavior recognition system to quantify food anticipatory activity in mice receiving 2, 3, or 6 daily meals at intervals of 12, 8, or 4-hours (h). Individual mice were able to anticipate as many as 4 of 6 daily meals, and anticipation persisted during meal omission tests. On the 6 meal schedule, pre-prandial activity and body temperature were poorly correlated, suggesting independent regulation. Mice showed a limited ability to anticipate an 18 h feeding schedule. Finally, mice showed concurrent circadian and sub-hourly anticipation when provided with 6 small meals, at 30 minute intervals, at a fixed time of day. These results indicate that mice can anticipate feeding opportunities at a fixed time of day across a wide range of intervals not previously associated with anticipatory behavior in studies of rats. The methods described here can be exploited to determine the extent to which timing of different intervals in mice relies on common or distinct neural and molecular mechanisms.