Responses of cells in the rat suprachiasmatic nucleus in vivo to stimulation of afferent pathways are different at different times of the light/dark cycle

Conventional extracellular recordings were made from single cells in the suprachiasmatic nucleus (SCN) region of the anaesthetized rat. Each cell was tested for its response to stimulation at three sites; the contralateral optic nerve, the ipsilateral supraoptic nucleus (SON) or the ipsilateral arcuate nucleus (ARC) to determine whether the behaviour of the synapses in the SCN was different at different times. Responses to stimulation were tested once each hour and assessed by creating peristimulus time histograms. Excitatory, inhibitory or complex (consisting of more than one component) responses were seen. The responses of some cells that were recorded for several hours changed with time. Changes were seen in the responses of SCN cells to stimulation of the ARC (31/91 cells) and the SON (26/90 cells) regions, but only rarely to stimulation of the optic nerve (2/72 cells). Such differences in proportion are unlikely to have occurred by chance (P < 0.001; chi-square test). Changes seen included the appearance of both excitatory and inhibitory responses in cells that were initially unresponsive. In some cells, one component of a complex response remained constant while another component changed with time. When the cells in the SCN were treated as a group, the proportion of excitatory, inhibitory or complex responses to ARC stimulation did not remain constant throughout the light/dark cycle (P = 0.014; chi-square test). The proportion of excitatory, inhibitory or complex responses to SON and optic nerve stimulation showed no significant variation with the light/dark cycle. If a change in response can be interpreted as a change in the behaviour of a neural connection, the results imply that some of the projections to the SCN from within the hypothalamus change at different times of the light/dark cycle, whereas no change could be seen in the input from the optic nerve. Thus, some of the connections of the SCN appear not to be hard wired, but change rapidly with time.     

Projections of the suprachiasmatic nucleus to stress-related areas in the rat hypothalamus: A light and electron microscopic study

The purpose of the present study was to investigate the sites in the hypothalamus where the suprachiasmatic nucleus (SCN) may influence corticosteroid secretion. In spite ofthe well established, SCN-mediated, daily rhythms in adrenocorticotrophic hormone (ACTH) and corticosteroid secretion, previous studies determining the projections of the suprachiasmatic nucleus faiied to illustrate direct connections with corticotrophin-releasing hormone neurons (CRH). In order to identify where in the central nervous System the SCN may influence corticosteroid secretion, areas were selected that contained SCN efferents contacting neurons involved in the stress response. To achieve this in the present study, SCN efferents were visualized by Pha-L tract-tracing, together with the neurons involved in the stress response by immunocytochemical staining for c-fos protein. The sites where these efferents contacted c-fos-positive neurons were established by light microscopic double staining and electron microseopic immunocytochemical studies. It appeared that apart from the medial parvocellular area of the paraventrieular nucleus (PVN) of the hypothalamus, many more regions showed fos-positive neurons. Sites where SCN efferents contacted such neurons are limited only to areas immediately adjacent to these putative CRH neurons but are not concentrated on these neurons themselves. These areas consist of the periventricular and rostral PVN together with the dorsomedial hypothalamus: all three regions are known to project into the PVN. Therefore, it is concluded that the SCN transmits its Information related to corticosteroid secretion via interneurons in and around the PVN to the CRH-containing neurons, rather than by a direct interaction with these neurons themselves. © 1993 Wiley-Liss, Inc.     

Functional D1 and D5 dopamine receptors are expressed in the suprachiasmatic,supraoptic, and paraventricular nuclei of primates

In rodents, D1 dopamine receptors are expressed in the suprachiasmatic nucleus and are believed to play important roles in regulating circadian rhythms. It is not currently known if the primate circadian system can be influenced by dopaminergic agents, which have broad clinical use. To determine if dopamine receptors can potentially influence primate circadian function, we examined the expression of D1 dopamine receptors in the anterior hypothalamus of ring-tailed macaques (Macaca nemestrema), baboons (Papio sp.), and humans. Because D5 dopamine receptors also stimulate adenylyl cyclase activity, D5 dopamine receptor expression was studied as well. We used [¹²⁵I]SCH 23982, which binds to D1 and D5 dopamine receptors, and labeling of the suprachiasmatic (SCN), supraoptic (SON), and paraventricular (PVN) nuclei was detectable in each species. In situ hybridization studies revealed differential expression of D1 and D5 dopamine receptor mRNA in the hypothalamus. D1 dopamine receptor mRNA was expressed in the SCN, SON, and PVN. By contrast, D5 dopamine receptor mRNA was expressed only in the SON and PVN of baboons and humans. Injection of the D1/D5 dopamine receptor agonist SKF 38393 at night increased the uptake of 2-deoxy-D-[¹⁴C]glucose in the SCN, SON, and PVN of newborn baboons. By contrast, c-fos mRNA expression was induced in the SON and PVN, but not in the SCN. These data show that D1 and D5 dopamine receptors are present in the hypothalamus of primates and show that activation of these receptors acutely influences SCN, SON, and PVN activity. Synapse 26:1–10, 1997. © 1997 Wiley-Liss, Inc.     

Distribution of vasopressin and vasoactive intestinal polypeptide (VIP) fibers in the human hypothalamus with special emphasis on suprachiasmatic nucleus efferent projections

The human suprachiasmatic nucleus (SCN) is located in the basal part of the anterior hypothalamus and is considered as the biological clock that generates circadian rhythms and synchronizes the daily activity pattern with the environmental light-dark cycle. However, the mechanisms and pathways by which the SCN transmits its information to the other brain areas are unknown. Therefore, in the present study, we investigated the efferent projections of the SCN by the immunocytochemical staining of two major peptidergic SCN neurotransmitters: vasopressin (VP) and vasoactive intestinal polypeptide (VIP). It confirmed that these peptides are present in different subdivisions of the SCN. The results of this investigation show that VP and VIP fibers arising from the SCN were detected to branch extensively and hence seem to innervate the SCN itself and the central and medial part of the anteroventral hypothalamic area (AVH), the area below the paraventricular nucleus (sub-PVN), the ventral part of the paraventricular nucleus (PVN), and the dorsomedial nucleus of the hypothalamus (DMH). There appeared to be substantial congruity between the presumptive human SCN projections and those as observed by tracing in rat or hamster. Regarding the anatomical organization of the human SCN projections, the main projection areas appeared to be the AVH, the sub-PVN, the ventral part of the PVN, and the DMH. The observation that VIP and in particular VP fibers pass between the SCN and the PVN suggests that the human SCN and the PVN may have a direct anatomical connection. In addition, VP and VIP fibers were detected in several other hypothalamic areas that are not known to have clear direct connections to the SCN. The possible origin of these VP and VIP fibers is discussed. J. Comp. Neurol. 383:397-414, 1997. © 1997 Wiley-Liss, Inc.     

Effects of lesions in the hypothalamic paraventricular, supraoptic and suprachiasmatic nuclei on vasopressin and oxytocin in rat brain and spinal cord

The content of arginine vasopressin and oxytocin in various extrahypothalamic sites of the rat brain and spinal cord was determined by specific radioimmunoassays after lesions had been made in either the paraventricular (PVN), supraoptic (SON) or suprachiasmatic nuclei (SCN). In some animals all 3 nuclei were destroyed together. The PVN provided a considerable amount of the vasopressin innervation of the solitary tract nucleus, and most of that in the spinal cord. Oxytocin was removed from some areas after lesions of the PVN and, again, most of this peptide was lost from the spinal cord. Lesions of the SCN did not appear to be followed by significant quantitative changes in either hormone in any of the areas studied. Lesions of the SON resulted in loss of oxytocin, particularly in the periventricular grey and some other areas, suggesting that extrahypothalamic projections from this nucleus may be more important than was previously assumed. Lesions of all 3 nuclei which included destruction of accessory hypothalamic nuclei resulted in a much more widespread loss of vasopressin and oxytocin, but there was preservation of both peptides in the dorsal raphe nucleus and much of those present in the locus coeruleus. It is concluded that the contribution of the classical hypothalamic nuclei to the extrahypothalamic content of vasopressin and oxytocin in rat brain is less than was originally believed, and that there are areas of the brain such as the locus coeruleus and dorsal raphe nucleus in which the source of these peptides may be outside the hypothalamus.     

Photic regulation of circadian rhythms and the expression of p75 neurotrophin receptor immunoreactivity in the suprachiasmatic nucleus in rats

Neurotrophic factors have been implicated in the mechanism underlying photic regulation of circadian rhythms in mammals. In rats, the most abundant neurotrophin receptor found in the suprachiasmatic nucleus (SCN), the circadian clock, is the low affinity p75 neurotrophin receptor (p75NTR). This receptor is expressed by retinal afferents of the SCN, but nothing is known about its role in photic regulation of circadian rhythms. We show here that neonatal treatment with the retinal neurotoxin, monosodium glutamate (MSG), which has no effect on photic entrainment of circadian rhythms, nearly completely abolished p75NTR immunoreactivity in the SCN in rats. These findings suggest that p75NTR from retinal sources do not play an essential role in the mechanism mediating photic entrainment of circadian rhythms in rats.     

Ageing and the diurnal expression of the mRNAs for vasopressin and for the V1a and V1b vasopressin receptors in the suprachiasmatic nucleus of male rats

Changes in the function of neuropeptide synthesizing cells within the suprachiasmatic nucleus (SCN), the site of the predominant circadian pacemaker, may underlie the disturbance of rhythms observed during ageing. Arginine vasopressin (AVP) is synthesized by nearly one-third of SCN neurones in the rat. This peptide has predominantly excitatory actions within the SCN mediated by V(1)-type receptors; the extent to which the V(1a) and/or V(1b) receptor subtypes are involved in SCN functions remains to be determined. The present study used isotopic in situ hybridization histochemistry to examine the effects of ageing on expression of mRNAs for AVP and V(1a) in the SCN and for V(1b) in the SCN and supraoptic nucleus (SON) of male rats kept under a 12 : 12 h light/dark cycle. Analysis of film autoradiographs from young adult (2-3-month-old; n = 40) or aged (19-20-month-old; n = 40) animals, at eight time points across the light/dark cycle, revealed an equivalent pattern and amplitude for the diurnal rhythm of AVP mRNA in the SCN of the young adult and aged groups. Both groups also displayed a significant diurnal rhythm in the expression of V(1a) receptor mRNA; however, the amplitude of this rhythm was reduced in the aged group, due to increased levels during the light phase and early part of night. Although the expression of V(1b) mRNA did not display a significant diurnal rhythm within the SCN or SON, persistently elevated levels for V(1b) mRNA were observed in the aged group at both sites.     

Distribution of thyrotropin-releasing hormone (TRH)-containing cells and fibers in the human hypothalamus

In the present study, we describe for the first time the distribution of thyrotropin-releasing hormone (TRH)-containing cells and fibers in the human hypothalamus using brain material obtained with a short postmortem delay. Following fixation in paraformaldehyde, glutaraldehyde and picric acid, excellent staining was obtained with two different TRH antisera. Many TRH-containing neurons were present in the paraventricular nucleus (PVN), especially in the dorsocaudal part of this nucleus. They were mostly parvicellular, but a few magnocellular TRH-positive neurons were observed as well. The PVN also contained a dense network of TRH fibers. The supraoptic nucleus (SON) did not show any TRH immunoreactivity, excluding the possibility of cross-reactivity of the antiserum with neurohypophysial hormones or their precursors. In addition, TRH cells were found in the suprachiasmatic nucleus (SCN), which is the circadian clock of the brain, in the sexually dimorphic nucleus (SDN) and dorsomedially of the SON. We observed small numbers of TRH cells throughout the hypothalamic gray in all subjects studied. A high density of TRH-containing fibers was seen not only in the median eminence but also in other hypothalamic areas, e.g., in the ventromedial nucleus (VM) and in the perifornical area. The results generally agree with earlier data in the rat, with the exception of the absence of TRH cells in the SON. The large number of sites of TRH-containing fiber terminations on neurons suggests important physiological functions of this neuropeptide as a neurotransmitter or neuromodulator in the human brain in addition to its role as a neurohormone in pituitary secretion of thyroid-stimulating hormone (TSH).     

Suprachiasmatic nucleus and retinohypothalamic projections in moles.

The suprachiasmatic nucleus of the hypothalamus (SCN) and the retinohypothalamic projections were identified in one species of old-world moles, all of whom are blind as a result of natural loss of vision. A cyto-architectonic study revealed that the SCN is well developed, even though other visual nuclei in the dorsal thalamus and the midbrain are not. An immunohistochemical study showed that vasoactive intestinal polypeptide (VIP)-like immunoreactive cell bodies and fibers were distributed in the SCN, as has been reported in other mammals. Following intraocular injections of wheatgerm agglutinin conjugated to horseradish peroxidase (WGA-HRP), the central retinal projections were examined. The results indicated that the SCN receives a direct projection from the retina, as seen in many other mammals. In addition to the projection to the SCN, retinal fibers were seen to terminate in the anterior hypothalamic region and the retrochiasmatic area, as observed in some other mammals. In moles, retinohypothalamic projections are bilateral, with an ipsilateral predominance. Considering that the retinogeniculate and retinotectal projections are vestigial, it is highly probable that the optic pathway in moles primarily consists of retinohypothalamic projections, which are devoted to the entrainment of circadian and circannual rhythms.     

Retinal input to the suprachiasmatic nucleus before and after puberty in Djungarian hamsters

Retinal projections to the suprachiasmatic nucleus (SCN) mediate the effect of photoperiod to entrain circadian rhythms and to control reproductive maturation in the Djungarian hamster. To determine whether the retinal innervation of the SCN had fully developed by the onset of puberty in this hamster species, prepubertal and postpubertal hamsters received an intraocular unilateral injection of horseradish peroxidase (HRP), and after 24 h, the anterograde transport of HRP to the SCN was studied. In prepubertal hamsters, the retinohypothalamic tract (RHT) was found to project to the medial and caudal SCN, principally the ventrolateral regions and, to an extent, the dorsomedial portion of the nucleus. RHT innervation was asymmetric; the SCN contralateral to the monocular injection received the dominant projection. A similar pattern of retinal projections was found postpubertally; however, the ipsilateral SCN was less extensively labelled with HRP and smaller as determined by Nissl counterstain compared to that in prepubertal hamsters. These findings indicate that modifications in the retinal innervation of the SCN occur as late as puberty, and may be part of a developmental change in the mechanism which processes photoperiodic information during sexual maturation.     

A combined electron microscopic HRP and immunocytochemical study of the limbic projections to rat hypothalamic nuclei containing vasopressin and oxytocin neurons

Light microscopic studies in our laboratory have indicated that the lateral septum, amygdala, and ventral subiculum project in a perinuclear fashion to the paraventricular (PVN), supraoptic (SON), and suprachiasmatic (SCN) nuclei (Oldfield et al., '82; Silverman and Oldfield, '84). In the present paper a combined anterograde HRP and immunocytochemical procedure has been used to determine the connectivity between these limbic efferents and peptide-containing processes emanating from the above mentioned hypothalamic nuclei. Synaptic associations were found to exist between efferents from (1) the septum and both vasopressin (VP)- and oxytocin (OX)-positive dendrites derived from cells in the PVN and SON, (2) the septum and VP dendrites dorsal to the SCN, (3) the ventral subiculum and both VP and OX dendrites arising from the PVN and SON, and (iv) the amygdala and VP dendrites from the PVN. These observations help clarify an apparent discrepancy between electrophysiological data, in which limbic efferents have been shown to influence the activity of VP and OX neurons in the PVN and SON, and anatomical evidence which indicates only a perinuclear innervation from these sites not encroaching on the hypothalamic nuclei themselves. In each case the synaptic connections are made on dendrites external to the nucleus: those lateral and ventrolateral to the PVN, dorsal to the SON, and dorsal or dorsolateral to the SCN.     

Responses of cells in the rat supraoptic nucleus in vivo to stimulation of afferent pathways are different at different times of the light/dark cycle

To determine whether the daily rhythms of spike activity in the supraoptic nucleus (SON) were accompanied by changes in the behaviour of its inputs, we used conventional extracellular single cell recordings from cells in the SON of anaesthetized rats while stimulating the contralateral optic nerve and the ipsilateral suprachiasmatic nucleus (SCN). Neurones in the SON region were identified by antidromic activation and classified as oxytocin or vasopressin cells, on the basis of their spontaneous firing patterns. Approximately 27% of both oxytocin (29/108) and vasopressin (39/147) neurones were excited by stimulation of the optic nerve, and the majority of responses had a long latency (>20 ms). Very few oxytocin (3/108) and vasopressin cells (2/147) were inhibited by stimulation of the optic nerve. The pattern of the responses (excitatory, inhibitory or nonresponsive) of oxytocin and vasopressin cells to stimulation of the optic nerve was significantly related to the time of day (chi-square test; P = 0.012, oxytocin cells; P = 0.006, vasopressin cells). The proportion of oxytocin cells excited by stimulation of the optic nerve was highest at ZT 4-8 and lowest at ZT 20-24. For vasopressin cells, it was highest at ZT 12-16 and lowest at ZT 20-24. The proportion of excitatory, inhibitory and complex responses seen in oxytocin and vasopressin cells following stimulation of the SCN also changed and was significantly different at different times of day (oxytocin cells: highest proportion of excitatory responses at ZT 12-16, P = 0.029; chi-square test; vasopressin cells: highest proportion of excitatory responses at ZT 0-4, P = 0.005; chi-square test). Thus, inputs to oxytocin and vasopressin neurones from the optic nerve and some outputs from the SCN changed during the light/dark cycle. Such changes may contribute to the generation of 24-h rhythms in activity of oxytocin and vasopressin neurones and release of the peptides.     

Effect of 192 IgG-saporin on circadian activity rhythms,expression of P75 neurotrophin receptors,calbindin-D28K,and light-induced Fos in the suprachiasmatic nucleus in rats

Photic entrainment of circadian rhythms in mammals is mediated through a direct retinal projection to the core region of the suprachiasmatic nucleus (SCN), the circadian clock. A proportion of this projection contains the low-affinity p75 neurotrophic receptor (p75NTR). Neonatal monosodium glutamate (MSG) treatment, which dramatically reduces p75NTR immunoreactivity in the SCN has no impact on photic entrainment. In order to clarify the contribution of p75NTR fibers in photic entrainment, targeted lesions of the p75NTR-immunoreactive SCN plexus were performed using intracerebroventricular (ICV) or intrahypothalamic injections of the immunotoxin 192 IgG-saporin (SAP) in rats. SAP treatment effectively abolished p75NTR immunoreactivity within the SCN core. ICV SAP treatment produced three different behavioral activity patterns: Animals became arrhythmic, displayed a shorter free-running period, or remained rhythmic following the lesion. Arrhythmic animals had large hypothalamic lesion which encompassed the entire SCN. In rhythmic rats, ICV-SAP significantly reduced immunostaining for calbindin-D28k (CaBP) in the SCN, and rats with shortened free-running periods had the lowest number of CaBP immunoreactive cells. ICV SAP also attenuated light-induced Fos expression in the SCN core. Despite lack of p75NTR and reduced CaBP and Fos expression in the SCN, SAP-treated rhythmic rats displayed normal photic entrainment. Intrahypothalamic SAP treatment reduced CaBP expression in the SCN but had no effect on light-induced Fos expression, free-running rhythms, or photic entrainment. The data show that p75NTR-immunoreactive elements in the SCN are not required for photic entrainment.     

Site of origin of and sex differences in the vasopressin innervation of the mouse (Mus musculus) brain

Defining how arginine vasopressin (AVP) acts centrally to regulate homeostasis and behavior is problematic, as AVP is made in multiple nuclei in the hypothalamus (i.e., paraventricular [PVN], supraoptic [SON], and suprachiasmatic [SCN]) and extended amygdala (i.e., bed nucleus of the stria terminalis [BNST] and medial amygdala [MeA]), and these groups of neurons have extensive projections throughout the brain. To understand the function of AVP, it is essential to know the site of origin of various projections. In mice, we used gonadectomy to eliminate gonadal steroid hormone–dependent expression of AVP in the BNST and MeA and electrolytic lesions to eliminate the SCN, effectively eliminating those AVP‐immunoreactive projections; we also quantified AVP‐immunoreactive fiber density in gonadectomized and sham‐operated male and female mice to examine sex differences in AVP innervation. Our results suggest that the BNST/MeA AVP system innervates regions containing major modulatory neurotransmitters (e.g., serotonin and dopamine) and thus may be involved in regulating behavioral state. Furthermore, this system may be biased toward the regulation of male behavior, given the numerous regions in which males have a denser AVP‐immunoreactive innervation than females. AVP from the SCN is found in regions important for the regulation of hormone output and behavior. Innervation from the PVN and SON is found in brain regions that likely work in concert with the well‐known peripheral AVP actions of controlling homeostasis and stress response; female‐biased sex differences in this system may be related to the heightened stress response observed in females. J. Comp. Neurol. 521:2321–2358, 2013. © 2012 Wiley Periodicals, Inc.     

Ultrastructural evidence for intra- and extranuclear projections of GABAergic neurons of the suprachiasmatic nucleus

GABAergic projections of the suprachiasmatic nucleus (SCN) were demonstrated in a double-labelling ultrastructural study which visualised the efferents of the SCN by PHA-L tracing, diaminobenzidine (DAB) immunocytochemistry, and GABA with immunogold postembedding staining. The results show a strong contralateral projections of the SCN that is partly GABA-containing. In addition, ipsilateral SCN projections to the dorsomedial hypothalamus and periventricular part of the paraventricular nucleus and subparaventricular nucleus were shown to contain GABA. The present results indicate that the SCN may utilize this inhibitory neurotransmitter to regulate and organize its own circadian rhythm as well as using GABA to transmit its diurnal information to other regions of the brain. © Wiley-Liss, Inc.     

Neuron numbers in the hypothalamus of the normal aging rhesus monkey: stability across the adult lifespan and between the sexes

Normal aging is accompanied by changes in hypothalamic functions including autonomic and endocrine functions and circadian rhythms. The rhesus monkey provides an excellent model of normal aging without the potential confounds of incipient Alzheimer's disease inherent in human populations. This study examined the hypothalamus of 51 rhesus monkeys (23 male, 18 female, 6.5-31 years old) using design-based stereology to obtain unbiased estimates of neuron and glia numbers and the Cavalieri method to estimate volumes for eight reference spaces: total unilateral hypothalamus, suprachiasmatic nucleus (SCN), supraoptic nucleus (SON), paraventricular nucleus (PVN), dorsomedial nucleus (DM), ventromedial nucleus (VM), medial mammillary nucleus (MMN), and lateral hypothalamic area (LHA). The results demonstrated no age-related difference in neuron number, glia number, or volume in any area in either sex except the PVN of male monkeys, which showed a significant increase in both neuron and glia numbers with age. Comparison of males and females for sexual dimorphisms revealed no significant differences in neuron number. However, males had more glia overall as well as in the SCN, DM, and LHA and had a larger hypothalamic volume overall and in the SCN, SON, VM, DM, and MMN. These results demonstrate that hypothalamic neuron loss cannot account for age-related deficits in hypothalamic function and provides further evidence of the absence of neurodegeneration and cell death in the normal aging rhesus monkey.     

Central projections of melanopsin-expressing retinal ganglion cells in the mouse

A rare type of ganglion cell in mammalian retina is directly photosensitive. These novel retinal photoreceptors express the photopigment melanopsin. They send axons directly to the suprachiasmatic nucleus (SCN), intergeniculate leaflet (IGL), and olivary pretectal nucleus (OPN), thereby contributing to photic synchronization of circadian rhythms and the pupillary light reflex. Here, we sought to characterize more fully the projections of these cells to the brain. By targeting tau-lacZ to the melanopsin gene locus in mice, ganglion cells that would normally express melanopsin were induced to express, instead, the marker enzyme beta-galactosidase. Their axons were visualized by X-gal histochemistry or anti-beta-galactosidase immunofluorescence. Established targets were confirmed, including the SCN, IGL, OPN, ventral division of the lateral geniculate nucleus (LGv), and preoptic area, but the overall projections were more widespread than previously recognized. Targets included the lateral nucleus, peri-supraoptic nucleus, and subparaventricular zone of the hypothalamus, medial amygdala, margin of the lateral habenula, posterior limitans nucleus, superior colliculus, and periaqueductal gray. There were also weak projections to the margins of the dorsal lateral geniculate nucleus. Co-staining with the cholera toxin B subunit to label all retinal afferents showed that melanopsin ganglion cells provide most of the retinal input to the SCN, IGL, and lateral habenula and much of that to the OPN, but that other ganglion cells do contribute at least some retinal input to these targets. Staining patterns after monocular enucleation revealed that the projections of these cells are overwhelmingly crossed except for the projection to the SCN, which is bilaterally symmetrical.     

Brain-derived neurotrophic factor and neurotrophin receptors modulate glutamate-induced phase shifts of the suprachiasmatic nucleus

Light information reaches the suprachiasmatic nucleus (SCN) through a subpopulation of retinal ganglion cells. Previous work raised the possibility that brain-derived neurotrophic factor (BDNF) and its high-affinity tropomyosin-related receptor kinase may be important as modulators of this excitatory input into the SCN. In order to test this possibility, we used whole-cell patch-clamp methods to measure spontaneous excitatory currents in mouse SCN neurons. We found that the amplitude and frequency of these currents were increased by BDNF and decreased by the neurotrophin receptor inhibitor K252a. The neurotrophin also increased the magnitude of currents evoked by application of N-methyl-d-aspartate and amino-methyl proprionic acid. Next, we measured the rhythms in action potential discharge from the SCN brain slice preparation. We found that application of K252a dramatically reduced the magnitude of phase shifts of the electrical activity rhythm generated by the application of glutamate. By itself, BDNF caused phase shifts that resembled those produced by glutamate and were blocked by K252a. The results demonstrate that BDNF and neurotrophin receptors can enhance glutamatergic synaptic transmission within a subset of SCN neurons and potentiate glutamate-induced phase shifts of the circadian rhythm of neural activity in the SCN.