We all have a sense of time. Yet, there are no sensory receptors specifically dedicated for perceiving time. It is an almost uniquely intangible sensation: we cannot see time in the way that we see color, shape, or even location. So how is time represented in the brain? We explore the neural substrates of metrical representations of time such as duration estimation (explicit timing) or temporal expectation (implicit timing). Basal ganglia (BG), supplementary motor area, cerebellum, and prefrontal cortex have all been linked to the explicit estimation of duration. However, each region may have a functionally discrete role and will be differentially implicated depending upon task context. Among these, the dorsal striatum of the BG and, more specifically, its ascending nigrostriatal dopaminergic pathway seems to be the most crucial of these regions, as shown by converging functional neuroimaging, neuropsychological, and psychopharmacological investigations in humans, as well as lesion and pharmacological studies in animals. Moreover, neuronal firing rates in both striatal and interconnected frontal areas vary as a function of duration, suggesting a neurophysiological mechanism for the representation of time in the brain, with the excitatory-inhibitory balance of interactions among distinct subtypes of striatal neuron serving to fine-tune temporal accuracy and precision.

The emergence of small open reading frame (sORF)-encoded peptides (SEPs) is rapidly expanding the known proteome at the lower end of the size distribution. Here, we show that the mitochondrial proteome, particularly the respiratory chain, is enriched for small proteins. Using a prediction and validation pipeline for SEPs, we report the discovery of 16 endogenous nuclear encoded, mitochondrial-localized SEPs (mito-SEPs). Through functional prediction, proteomics, metabolomics and metabolic flux modeling, we demonstrate that BRAWNIN, a 71 a.a. peptide encoded by C12orf73, is essential for respiratory chain complex III (CIII) assembly. In human cells, BRAWNIN is induced by the energy-sensing AMPK pathway, and its depletion impairs mitochondrial ATP production. In zebrafish, Brawnin deletion causes complete CIII loss, resulting in severe growth retardation, lactic acidosis and early death. Our findings demonstrate that BRAWNIN is essential for vertebrate oxidative phosphorylation. We propose that mito-SEPs are an untapped resource for essential regulators of oxidative metabolism.

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Choline availability in the maternal diet has a lasting effect on brain and behavior of the offspring. To further delineate the impact of early nutritional status, we examined effects of prenatal-choline supplementation on timing, emotion, and memory performance of adult male and female rats. Rats that were given sufficient choline (CON: 1.1 g/kg) or supplemental choline (SUP: 5.0 g/kg) during embryonic days (ED) 12-17 were trained with a differential reinforcement of low-rate (DRL) schedule that was gradually transitioned through 5-, 10-, 18-, 36-, and 72-sec criterion times. We observed that SUP-females emitted more reinforced responses than CON-females, which were more efficient than both groups of males. In addition, SUP-males and SUP-females exhibited a reduction in burst responding (response latencies <2 sec) compared with both groups of CON rats. Furthermore, despite a reduced level of burst responding, the SUP-males made more nonreinforced responses prior to the DRL criterion as a result of maintaining the previous DRL criterion following transition to a new criterion. In summary, long-lasting effects of prenatal-choline supplementation were exhibited by reduced frustrative DRL responding in conjunction with the persistence of temporal memory in SUP-males and enhanced temporal exploration and response efficiency in SUP-females.Choline is an essential nutrient for the regulation of cell signaling, methyl metabolism, and acetylcholine synthesis in both the infant and adult (Zeisel and Niculescu 2006). It has been found that when choline is administered at levels higher than normal to pregnant rats during embryonic days (ED) 12-17, the adult offspring showed enhanced spatial and temporal memory (Meck and Williams 2003). Specifically, rats given this prenatal-choline supplementation made fewer errors when tested on a radial-arm maze (Meck et al. , 1989Meck and Williams 1999) and are able to chunk more information in spatial memory that helps them identify multiple-reward baiting patterns (Dallal and Meck 1990;Meck and Williams 1997b). Similarly, when challenged with tasks that require the ability to remember durations in the seconds-to-minutes range, prenatal choline-supplemented rats produced more precise timing functions and are better able to time multiple durations simultaneously compared with control rats (Meck and Williams 1997a,c;Cheng et al. 2006b). The prenatal availability of choline also modifies the development of the cholinergic system (e.g., Meck et al. 1989;Williams et al. 1998;Cermak et al. 1999;Montoya et al. 2000;Mellott et al. 2004) and alters indices of hippocampal plasticity (e.g., Pyapali et al. 1998;Glenn et al. 2007). Together, these findings indicate that prenatal-choline supplementation can induce profound changes in brain function that lead to increased memory capacity and precision in adult offspring. In the present study, the potential benefits of prenatal-choline supplementation were further investigated by using differential reinforcement of low-rate (DRL) schedules to study th...