Kuhlman, Sandra J., Rae Silver, Joseph Le Sauter, Abel Bult-Ito and Douglas G. McMahon. (in press) Phase Resetting Light Pulses Induce Per1 and Persistent Spike Activity. Journal of Neuroscience.

Hamada, T. Lesauter, J., Venuti, J. Silver, R. (2001). Expression of Period genes: Rhythmic and non-rhythmic compartments of the Suprachiasmatic Nucleus. J. Neurosci. 21:7742-50.

Lehman, M.N., Silver, R., Gladstone, W.R., Kahn, R.M., Gibson, M. and Bittman, E.L. (1987). Circadian rhythmicity restored by neural transplant. Immunocytochemical characterization of the graft and its integration with the host brain. J. Neurosci. 7: 1626-1638.

ABSTRACT:
Individual neurons within the mammalian suprachiasmatic nucleus contain a self-sustaining oscillatory mechanism. The basis for this oscillation is a transcriptional-translational feedback loop; e.g., an intracellular system in which gene products feed back to inhibit their own production. Genetic, biochemical and behavioral studies have contributed to our current understanding of the molecular mechanisms for circadian rhythmicity. These studies reveal that the core circadian oscillatory mechanism is made up of 1) a positive drive, coming from the basic helix-loop-helix/PAS transcription factors CLOCK and BMAL1, which promote the expression of Per1-3 and Cry1-2 genes and 2) a negative feedback component, resulting from the interaction of PER and CRY proteins with the CLOCK:BMAL1 complex. Additional mechanisms appear to stabilize rhythmicity, and adjust the cycle length, e.g., phosphorylation events and RevErb-alpha. Recently, gene targeting ("knockout") strategies have been applied to circadian genes. These studies support the importance of the genes within the feedback loop model described above, but also provide some unexpected results, including apparent redundancy of function. The results provide a useful vehicle for discussing the power, as well as the shortcomings, of gene targeting strategies in complex biological systems.

RELATED READINGS:
Reppert SM, Weaver DR (2002) Coordination of circadian timing in mammals. Nature 418: 935-941. (review)

Bae K, Jin X, Maywood ES, Hastings MH, Reppert SM, Weaver DR (2001). Differential functions of mPer1, mPer2, and mPer3 in the SCN circadian clock. Neuron 30: 525-536.

Albrecht U, Zheng B, Larkin D, Sun ZS, Lee CC. (2001) mPer1 and mPer2 are essential for normal resetting of the circadian clock. J Biol Rhythms 16:100-104.

Mar 28
WESLEY WHITE
Department of Psychology, Morehead State University
Title: Circadian Activity

ABSTRACT:
The psychomotor stimulant amphetamine (AMPH) can produce effects, such as increased alertness and a sense of well being, that promote its subsequent re-use. Repeated use of AMPH can produce a variety of syndromes including sensitization, tolerance, dependence, withdrawal, abuse, toxicity, and psychosis. In animal models, AMPH-induced syndromes have typically been studied by looking either at some immediate effect of AMPH (an effect occurring during the first several hours post-administration) or at some remote effect (an effect occurring 24 or more hours post-administration). The nature and implications of intermediate term effects of AMPH administration have received little attention. The purpose of the talk is to describe methods concerned with revealing, and ultimately understanding, the multiple time-dependent AMPH-induced effects that occur during the ca-24-hour interval subsequent to administration. Rats are housed in individual cubicles in a 12-12 hour light-dark cycle and have free access to food and water, and their simple open field activity is continuously monitored following saline or AMPH. One notable feature of the methodology is the manipulation of light-dark cycles and / or schedules of administration in a way such that the AMPH-induced pattern of activity can be visualized apart from the endogenous light-entrainable circadian rest-activity cycle. The methodology reveals a three-phase response to moderate and high doses of AMPH: 1) AMPH produces an immediate psychomotor stimulant state that lasts for several hours post-administration and that is indicated by hyperactivity; 2) It produces an acute withdrawal state that has maximum expression approximately 20 hours post-administration, that lasts for several hours, and that is indicated by hypo-activity; 3) It produces a recovery state that begins approximately 24 hours post-administration and that is reflected in either a normalization of activity or in a moderate activity rebound. A moderate dose of AMPH produces acute withdrawal after several administrations, whereas higher doses produce acute withdrawal after a single administration. The time course of acute withdrawal does not appear to depend on dose. Hypo-activity near hour 20 post-AMPH-administration appears to be a marker of a withdrawal state, because other withdrawal-like symptoms (REM sleep rebound, dysphoria, unwillingness to work for natural rewards, and hypothermia) also occur near hour 20. The withdrawal-like effects seen at hour 20 are "opposite in sign" compared to AMPH's immediate effects. This observation suggests that a unitary mechanism could be involved in the induction of the sequence of AMPH-induced states, as does the indication that several variables undergo a correlated change during the ca-24-hour interval following AMPH. Many of the immediate effects of AMPH are mediated by dopamine (DA) receptors and by nuclei in the dopaminergic systems. To determine whether the hypothetical unitary mechanism was the DA receptor, we administered the selective direct DA agonist apomorphine. In another study we micro-infused AMPH directly into the nucleus accumbens (NA). Both manipulations appeared to reproduce important features of the AMPH-induced activity pattern. These preliminary results suggest that DA and the NA may have a role, not only in AMPH's immediate effects, but also in acute withdrawal and recovery. The methodology may have applicability in the study of depression, drug relapse, time-dependent susceptibility to drug, and drug-induced changes in motivation.

RELATED READINGS:
White, W., Feldon, J., Heidbreder, C. A., & White, I. M. (2000). Effects of administering cocaine at the same versus varying times of day on circadian activity patterns and sensitization in rats. Behavioral Neuroscience, 114, 972-982.
White, W., & Timberlake, W. (1999). Meal-engendered circadian ensuing activity in rats. Physiology & Behavior, 65, 625-642.
Barr, A. M., & Phillips, A. G. (1999). Withdrawal following repeated exposure to d-amphetamine decreases responding for a sucrose solution as measured by a progressive ratio schedule of reinforcement. Psychopharmacology, 141, 99-106.
Barrett, R. J., White, D. K., & Caul, W. F. (1992). Tolerance, withdrawal, and supersensitivity to dopamine mediated cues in a drug-drug discrimination. Psychopharmacology, 109, 63-67.
Edgar, D. M., & Seidel, W. F. (1997). Modafinil induces wakefulness without intensifying motor activity or subsequent rebound hypersomnolence in the rat. The Journal of Pharmacology and Experimental Therapeutics, 283: 757-769.
Koob, G. F., Caine, S. B., Parsons, L., Markou, A., & Weiss, F. (1997). Opponent process model and psychostimulant addiction. Pharmacology, Biochemistry, and Behavior, 57, 513-521

Apr 25
MICHAELA HAU
Dept of Ecology and Evolutionary Biology, Princeton University
Title: Ecology and evolution of physiological systems-tropical birds as model organisms.

ABSTRACT:
Animals need to adjust reproductive decisions to environmental seasonality. The environmental cues and the physiological mechanism which animals from mid and higher latitudes use to regulate reproduction have been well studied. In contrast, only little is known for tropical latitudes, where most species are found. I am investigating the endocrine mechanisms that regulate reproduction in spotted antbirds from the Panamanian rainforest and in small ground finches from the arid Galapagos islands. Spotted antbirds live in a fairly predictable seasonal environment and show regular changes in gonad sizes and hormone titers. They may use the same photoperiodic cues as mid and high latitude species, in spite of the very small annual variation in photoperiod close to the equator. However, spotted antbirds also respond strongly to seasonal food availability suggesting a remarkable flexibility in adjustment to environmental conditions. Small ground finches exposed to rather unpredictable climate in Galapagos appear to breed whenever rains fall, and maintain regressed gonads during the rest of the year. Lack of physiological preparation for the breeding season and short-term responses to rain and food stimuli suggest a striking flexibility in the regulation of breeding in small ground finches. I suggest that tropical birds can serve as model systems to uncover endocrine adaptations to different environments. Unravelling the neuroendocrine mechanisms behind flexibility in reproductive timing will clarify whether differences found between temperate and tropical birds represent variations of the same basic mechanism or instead reflect fundamental divergence in physiological control systems.

RELATED READINGS:
Hau, M., M. Wikelski, and J. C. Wingfield. 1998. A neotropical forset bird can measure the slight changes in tropical photoperiod. Proc. R. Soc. Lond. B 265, 89-95.
Hau, M., M. Wikelski, K. K. Soma, J. C. Wingfield. 2000. Testosterone and year-round territorial aggression in a tropical bird. Gen. & Comp. Endocrinology 117, 20-33
Hau, M. 2001. Timing of breeding in variable environments: tropical birds as model systems. Hormones and Behavior 40, 281-290