Biomedical subjects

Martin R Ralph

Publications and source records attributed to Martin R Ralph.

9 recordsLinked to original sources

PubMed2006

The molecular gatekeeper Dexras1 sculpts the photic responsiveness of the mammalian circadian clock.

The mammalian master clock, located in the suprachiasmatic nucleus (SCN), is exquisitely sensitive to photic timing cues, but the key molecular events that sculpt both the phasing and magnitude of responsiveness are not understood. Here, we show that the Ras-like G-protein Dexras1 is a critical factor in these processes. Dexras1-deficient mice (dexras1-/-) exhibit a restructured nighttime phase response curve and a loss of gating to photic resetting during the day. Dexras1 affects the photic sensitivity by repressing or activating time-of-day-specific signaling pathways that regulate extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK). During the late night, Dexras1 limits the capacity of pituitary adenylate cyclase (PAC) activating peptide (PACAP)/PAC1 to affect ERK/MAPK, and in the early night, light-induced phase delays, which are mediated predominantly by NMDA receptors, are reduced as reported previously. Daytime photic phase advances are mediated by a novel signaling pathway that does not affect the SCN core but rather stimulates ERK/MAPK in the SCN shell and triggers downregulation of clock protein expression.

Animals↗

PubMed2005

Nerve growth factor-induced circadian phase shifts and MAP kinase activation in the hamster suprachiasmatic nuclei.

Circadian rhythms are entrained by light and by several neurochemical stimuli. In hamsters housed in constant darkness, i.c.v. administration of nerve growth factor (NGF) at various times in their circadian cycle produced phase shifts of locomotor activity rhythms that were similar in direction and circadian timing to those produced by brief pulses of light. Moreover, the effect of NGF and light were not additive, indicating signalling points in common. These points include the immediate-early gene c-fos and ERK1/2, a component of the mitogen-activated protein kinases (MAPK) family. NGF activates c-FOS and ERK1/2-MAPK in the suprachiasmatic nuclei, the site of a circadian clock in mammals, when administered during the subjective night but not during the day. The effect of NGF on ERK1/2 activation was not inhibited by the administration of MK-801, a glutamate/NMDA receptor antagonist. These results suggest that NGF, acting through MAPK activation, plays a role in photic entrainment of the mammalian circadian clock.

Analysis of Variance↗

PubMed2004

Blunted cortisol rhythm is associated with learning impairment in aged hamsters.

In mammals, the cognitive decline that accompanies unsuccessful aging is associated with circadian rhythm dysfunction and increased levels of circulating glucocorticoids. The possible causal relations among these factors are not known. To test for primary effects of circadian clock dysfunction versus increased glucocorticoid levels as contributors to age-related learning impairment, we measured cortisol and wheel-running rhythms along with context learning in aged hamsters (15-18 months). At this age, locomotor rhythms of learners and nonlearners were found to be indistinguishable. However, plasma cortisol levels were lower, and the amplitude of the cortisol rhythm was reduced in the impaired animals. These data suggest that age-related cognitive decline may be related more to a loss of hormone rhythmicity than to a loss of behavioral rhythmicity or an increase in hormone level.

Aging↗

PubMed2004

Dexras1 potentiates photic and suppresses nonphotic responses of the circadian clock.

Circadian rhythms of physiology and behavior are generated by biological clocks that are synchronized to the cyclic environment by photic or nonphotic cues. The interactions and integration of various entrainment pathways to the clock are poorly understood. Here, we show that the Ras-like G protein Dexras1 is a critical modulator of the responsiveness of the master clock to photic and nonphotic inputs. Genetic deletion of Dexras1 reduces photic entrainment by eliminating a pertussis-sensitive circadian response to NMDA. Mechanistically, Dexras1 couples NMDA and light input to Gi/o and ERK activation. In addition, the mutation greatly potentiates nonphotic responses to neuropeptide Y and unmasks a nonphotic response to arousal. Thus, Dexras1 modulates the responses of the master clock to photic and nonphotic stimuli in opposite directions. These results identify a signaling molecule that serves as a differential modulator of the gated photic and nonphotic input pathways to the circadian timekeeping system.

Animals↗

PubMed2004

Circadian modulation of performance on an aversion-based place learning task in hamsters.

In golden hamsters, the expression of a reward-conditioned place preference (CPP) is regulated in a circadian pattern such that the preference is exhibited strongly at the circadian time of prior training but not at other circadian times. We now report that the same "time-stamp" phenomenon is expressed following context conditioning with an aversive stimulus (conditioned place avoidance, CPA). Animals that were trained at a specific circadian time to discriminate between a "safe" context and one paired with foot shock, showed strong avoidance of the paired context at 24 and 48 h following the last training session, and showed no avoidance at 32 and 40 h following training. Circadian time is a feature that is learned during conditioning even though timing itself is not an explicit discriminative cue in these experiments. The results suggest that in hamsters, the emotional valence associated with the place where arousing stimulation (rewarding and aversive) is encountered is highest at the circadian time of occurrence. The golden hamster may be predisposed to anticipate the recurrence of arousing events at circa-24 h intervals.

Animals↗

PubMed2004

Neural stem cells show bidirectional experience-dependent plasticity in the perinatal mammalian brain.

Many of the effects of prenatal stress on the endocrine function, brain morphology, and behavior in mammals can be reversed by brief sessions of postnatal separation and handling. We have tested the hypothesis that the effects of both the prenatal and postnatal experiences are mediated by negative and positive regulation of neural stem cell (NSC) number during critical stages in neurodevelopment. We used the in vitro clonal neurosphere assay to quantify NSCs in hamsters that had experienced prenatal stress (maternal restraint stress for 2 hr per day, for the last 7 d of gestation), postnatal handling (maternal-offspring separation for 15 min per day during postnatal days 1-21), orboth. Prenatal stress reduced the number of NSCs derived from the subependyma of the lateral ventricle. The effect was already present at postnatal day 1 and persisted into adulthood (at least 14 months of age). Similarly, prenatal stress reduced in vivo proliferation in the adult subependyma of the lateral ventricle. Conversely, postnatal handling increased NSC number and reversed the effect of prenatal stress. The effects of prenatal stress on NSCs and proliferation and the effect of postnatal handling on NSCs did not differ between male and females. The findings demonstrate that environmental factors can produce changes in NSC number that are present at birth and endure into late adulthood. These changes may underlie some of the behavioral effects produced by prenatal stress and postnatal handling.

Animals↗

PubMed2004

Time of day modulation of conditioned place preference in rats depends on the strain of rat used.

In golden hamsters, the expression of a conditioned place preference (CPP) or avoidance (CPA) is regulated in a circadian pattern such that the preference and avoidance are exhibited strongly at the circadian time of prior training, but not at other circadian times. In the rat, reports are conflicting regarding whether time of day learning is evident. We investigated whether this conflict arises because different strains of rat have been used. In this experiment, Long Evans and Wistar rats were trained at a specific circadian time to discriminate between a context paired with food reward and an unpaired context. Animals were then tested for preference at the same or a different circadian time. Long Evans rats showed preference for the paired context at both times tested, whereas Wistar rats showed preference only when training and testing times matched. The results show that time of day learning can be generalized to rats using the Wistar strain.

Animals↗

PubMed2004

Reward and aversive stimuli produce similar nonphotic phase shifts.

Circadian rhythms in rodents respond to arousing, nonphotic stimuli that contribute to daily patterns of entrainment. To examine whether the motivational significance of a stimulus is important for eliciting nonphotic circadian phase shirts in Syrian hamsters (Mesocricetus auratus), the authors compared responses to a highly rewarding stimulus (lateral hypothalamic brain stimulation reward [BSR]) and a highly aversive stimulus (footshock). Animals were housed on a 14:10-hr light-dark cycle until test day, when they were given a 1-hr BSR session (trained animals) or a 1-mA electric footshock at 1 of 8 circadian times, and were maintained in constant dark thereafter. Both BSR pulses and footshock produced nonphotic phase response curves. These results support the hypothesis that arousal resulting from the motivational significance of a stimulus is a major factor in nonphotic phase shifts.

Animals↗

PubMed2002

The significance of circadian phase for performance on a reward-based learning task in hamsters.

In humans and animal models, circadian modulation of learning has been demonstrated on numerous tests. However, it is unclear which aspects of the cognitive process are rhythmically regulated. In these experiments, we used a conditioned place preference task in hamsters to ask whether memory acquisition (hypothesis 1) or memory recall and performance (hypothesis 2) were subject to circadian modulation. In golden hamsters, access to a running wheel has been used as a reward to condition a place preference, but when given unrestricted access to a wheel, animals perform most of their spontaneous running within a few hours each day or circadian cycle. This suggested that either the perceived reward value of the wheel changes through the day or that the response to this reward is temporally restricted. Contrary to the hypotheses, we found that learning was not tied to the time of training nor to the time of testing, but rather animals showed a preference for a reward-paired context only at the circadian time that training had taken place. Timing is not an explicit discriminative cue in these experiments. Hence, the learning mechanism must be predisposed to register circadian time as an attribute during context learning.

Animals↗