BIOLOGICAL RHYTHMS Neuroendocrine control: homeostatic responses and biological rhythms. A role for anticipation or feed-forward mechanisms or scheduled events. Biological rhythms and SCN: what are they and how have been approached (what are oscillators, entrainment, light and melatonin, central and peripheral clocks). SCN, running activity rhythm and ovulatory LH surge. SCN signal transduction. Rhythms, Reproduction, Immunity and Failures 39 S ∑ E

Rhythms, Reproduction and Immunity 38 S ∑ E REPRODUCTIVE CYCLICITY Male repro: a simpler way of control Menstrual cycles: ovary / uterine anatomy and cell types, follicular phase, ovulation, luteal phase, cyclicity Race events: removal of P4 negative feedback, follicular recruitment or FSH inducing its own receptors, pulsatile LH secretion a richer communication language, preovulatory E2 triggering the LH preovulatory surge GnRH network as basic model for cyclicity Contraception, pathology

Rhythms, Reproduction and Immunity 38 S ∑ E ENDOCRINE IMMUNE INTERACTIONS Introduction to the immune system: lymphatic system, its immune cellular components and communication signals The neuroendocrine - immune link: a reversal of reductionist approaches under- lies effects of immune system on CNS as well as of the CNS on the immune system. HPA axis and neuroendocrine - immune link: adjuvant-induced arthritis and other models, gonadal steroids and other neuroendocrine systems, disease suceptibility / mechanisms at CNS level

Rhythms, Reproduction, Immunity and their failures

Take Home Message (THM) It’s all in the timing: many clocks, many outputs. Panda S and Hogenesch JB (2004). Genomic Institute of Novartis Research Foundation and Dept of Neuropharmacology, Scripps Research Institute. J of Biological Rhythms 19 (5), , It is thought that circadian regulation of physiology and behavior imparts survival advantages to organisms that use clocks. In mammals, a master clock resident in the SCN synchronizes other central and peripheral oscillators to evoke this regulation. This master oscillator consists of interlocking transcriptional-translational feedback loops, and it regulates both core clock genes necessary for oscillator maintenance as well as specific output genes that directly or indirectly mediate physiology under circadian control. It is now clear that both neuroanatomic and molecular outputs of the clock are necessary for proper circadian clock function.

Biological rhythms darklight It is thought that circadian regulation of physiology and behavior imparts survival advantages to organisms that use clocks. darklightconstant darkness

(1) (2) (3) (4) (5) Biological rhythms In mammals, a master clock resident in the SCN synchronizes other central and peripheral oscillators to evoke physiological circadian regulation

Biological rhythms SCN This master oscillator consists of interlocking transcriptional-translational feedback loops where circadian day and circadian night genes interact

Rhythms and Reproduction Blinded rat with intact SCN have reproductive cycles Blinded rat with a lesioned SCN do not have reproductive cycles Regulation of both core clock genes and specific output genes mediate physiology under circadian control, such as reproductive activities The SCN is responsible for the precise timing of the LH surge: SCN lesions eliminates the ovarian cycle (behavior & LH surge). The LH surge maintains its exact relationship to the locomotor activity in a constant light environment, suggesting they are controlled by the same circadian mechanism. Lengthening / shortening of activity cycle by pharmacological treatment or light entrainment alters the estrous behavior and the LH surge. Pentobarbital in proestrous AM temporarily blocks the LH surge, which occurs at precisely the normal time the next day

GnRH neurons GnRH stimulatory inputs inhibitory inputs Hypothalamus ovulation Rhythms and Reproduction Integrator’s “balancing act” where ovulation and anovulation are only the extremes of the central integrators’ playfield, regulating reproductive activities

Endo - Immune Interaction Neurotransmiters, hormons and peptides regulate the immune response “from without”

Endo - Immune Interaction Neurotransmiters, hormons and peptides regulate the immune response “from within”. This regulation includes a two-way interaction between CNS and immune system

Endo - Immune Interaction cellular immunity inputs humoral immunity inputs Hypothalamus Immune response Integrator’s “balancing act” where cellular and humoral inputs are only the extremes of the central integrators’ playfieldregulating the immune response

Rhythms, Reproduction, Immunity and their failures

a) b) c) d) structurefunction Which, increase or decrease? How do you know? Parts to total? Two feedbacks and an absolute requirement? Rhythms, Reproduction, Immunity and their failures