Modulation of photic resetting in rats by lesions of projections to the suprachiasmatic nuclei expressing p75 neurotrophin receptor

Abstract

The suprachiasmatic nuclei of the hypothalamus (SCN) are the site of the master circadian clock in mammals. The SCN clock is mainly entrained by the light-dark cycle. Light information is conveyed from the retina to the SCN through direct, retinohypothalamic fibres. The SCN also receive other projections, like cholinergic fibres from basal forebrain. To test whether cholinergic afferents are involved in photic resetting, lesions of cholinergic projections were performed in rats with intracerebroventricular (i.c.v.) injections or intra-SCN microinjections of 192 IgG-saporin. When injected in the SCN, this immunotoxin destroys the cholinergic projections and retinohypothalamic afferents that express p75 low-affinity nerve growth factor (p75(NGF)) receptors. The extent of lesions in the basal forebrain and SCN was assessed by acetylcholinesterase histochemistry, p75(NGF) receptor, choline acetyl-transferase, calbindin-D28K and VIP immunocytochemistry. The intra-SCN treatment reduced light-induced phase advances by 30%, and induced a complete loss of forebrain and retinal afferents expressing p75(NGF) receptors within the SCN and a decrease of forebrain cholinergic neurons, most likely those projecting to the SCN. The i.c.v. treatment reduced light-induced phase advances by 40%, increased phase delays and led to extensive damage of forebrain p75(NGF)-expressing neurons, while sparing half of the fibres expressing p75(NGF) receptors (retinal afferents?) in the SCN. Because the integrity of forebrain p75(NGF)-expressing neurons appears to be critical in mediating the effects on light-induced phase advances, we therefore suggest that anterior cholinergic projections expressing p75(NGF) receptors modulate the sensitivity of the SCN clock to the phase advancing effects of light.

Time to Pay Attention: Attentional Performance Time-Stamped Prefrontal Cholinergic Activation, Diurnality, and Performance

“…The regulation and function of synchronized increases in cortical cholinergic activity may extend to basal forebrain cholinergic projections to the suprachiasmatic nucleus (SCN; Hut and Van der Zee, 2011; Erhardt et al, 2004). It is not known whether SAT performance activates basal forebrain cholinergic projections to the SCN in parallel to the increases in cholinergic neurotransmission in the cortex.…”

Interactions between cognition and circadian rhythms: Attentional demands modify circadian entrainment.

“…Lesion studies designed to de-afferent neocortical regions essential for task performance are necessary to test the role of top-down regulation in modulation of the circadian clock. Additional studies are addressing the hypothesis that increased ACh release from the basal forebrain circuits, specifically activated with SAT training (Kozak et al , 2006), directly influence the phase of activity entrainment via the anatomical connectivity that exists between the basal forebrain and the SCN (Erhardt et al , 2004; Madeira, Pereira, Silva, Cadete-Leite, & Paula-Barbosa, 2004). These studies, in combination with microdialysis experiments in task performing animals, should offer insight into how ACh is being regulated across discrete brain regions in anticipation of daily training.…”

“…Other non-retinal inputs to the SCN presumed to influence circadian rhythms include pyramidal projection neurons from neocortical regions involved in action selection and executive function (Hurley, Herbert, Moga, & Saper, 1991; Vertes, 2004), serotonergic neurons originating in the dorsal raphe nucleus (Edgar, Miller, Prosser, Dean, & Dement, 1993; Medanic & Gillette, 1992; Meyer-Bernstein & Morin, 1996; Ying & Rusak, 1994), and cholinergic projections from midbrain and basal forebrain nuclei (Bina & Rusak, 1996; Bina, Rusak, & Semba, 1993, 1997; Erhardt et al , 2004; Gillette et al, 2001). The role of cholinergic inputs, particularly from the basal forebrain, has remained unclear, although experimental in vivo and in vitro data suggest that acetylcholine (ACh) can significantly alter circadian rhythm expression.…”

Revisiting the cholinergic hypothesis in the development of Alzheimer's disease

“…To the best of my knowledge there have been few studies exploring the effects of cholinergic depletion of the basal forebrain on these functions. Bassant et al (1995) and Kapas et al (1996) (Moga, 1998;Erhardt et al, 2004). This is the first study designed to examine the effects of a specific MS/VDB cholinergic lesion on measure of circadian rhythmicity.…”