Intergeniculate Leaflet Lesions Research Articles

Superior Colliculus Lesions Lead to Disrupted Responses to Light in Diurnal Grass Rats (Arvicanthis niloticus).

The circadian system regulates daily rhythms of physiology and behavior. Although extraordinary advances have been made to elucidate the brain mechanisms underlying the circadian system in nocturnal species, less is known in diurnal species. Recent studies have shown that retinorecipient brain areas such as the intergeniculate leaflet (IGL) and olivary pretectal nucleus (OPT) are critical for the display of normal patterns of daily activity in diurnal grass rats (Arvicanthis niloticus). Specifically, grass rats with IGL and OPT lesions respond to light in similar ways to intact nocturnal animals. Importantly, both the IGL and OPT project to one another in nocturnal species, and there is evidence that these 2 brain regions also project to the superior colliculus (SC). The SC receives direct retinal input, is involved in the triggering of rapid eye movement sleep in nocturnal rats, and is disproportionately large in the diurnal grass rat. The objective of the current study was to use diurnal grass rats to test the hypothesis that the SC is critical for the expression of diurnal behavior and physiology. We performed bilateral electrolytic lesions of the SC in female grass rats to examine behavioral patterns and acute responses to light. Most grass rats with SC lesions expressed significantly reduced activity in the presence of light. Exposing these grass rats to constant darkness reinstated activity levels during the subjective day, suggesting that light masks their ability to display a diurnal activity profile in 12:12 LD. Altogether, our data suggest that the SC is critical for maintaining normal responses to light in female grass rats.

Serotonergic enhancement of circadian responses to light: role of the raphe and intergeniculate leaflet.

Light serves as the primary stimulus that synchronizes the circadian clock in the suprachiasmatic nucleus (SCN) to the external day/night cycle. Appropriately timed light exposure can reset the phase of the circadian clock. Some serotonergic drugs that bind to the serotonin 1A receptor can enhance phase shifts to light. The mechanism by which this potentiation occurs is not well understood. In this study, we examined where one of these drugs, 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione dihydrochloride (BMY7378), might be working in the hamster brain. Systemic (5 mg/kg), intra-dorsal raphe and intra-median raphe (both 15.6 nmol in 0.5 μL), but not intra-SCN (7.8 nmol or 15.6 nmol in 0.5 μL) injections of BMY7378 significantly potentiated phase shifts to light. Potentiation of photic shifts persisted when serotonergic innervation of the SCN was lesioned with infusions of the serotonin neurotoxin 5,7-dihydroxytryptamine into the SCN. Light-induced c-Fos expression in the rostral and caudal intergeniculate leaflet (IGL) was attenuated with systemic BMY7378, suggesting that the IGL may be involved in this response. Both complete IGL lesions and depletion of serotonergic innervation of the IGL prevented systemic BMY7378 from potentiating photic phase shifts. Together, these findings suggest that the mechanism by which BMY7378 enhances photic responses is by changing the activity of the raphe nuclei to influence how the IGL responds to light, which subsequently influences the SCN as one of its downstream targets. Identification of the network that underlies this potentiation could lead to the development of useful therapeutic interventions for treating sleep and circadian disorders.

Intergeniculate leaflet lesions result in differential activation of brain regions following the presentation of photic stimuli in Nile grass rats

The intergeniculate leaflet (IGL) plays an important role in the entrainment of circadian rhythms and the mediation of acute behavioral responses to light (i.e., masking). Recently, we reported that IGL lesions in diurnal grass rats result in a reversal in masking responses to light as compared to controls. Here, we used Fos as a marker of neural activation to examine the mechanisms by which the IGL may influence this masking effect of light in grass rats. Specifically, we examined the patterns of Fos activation in retinorecipient areas and in brain regions that receive IGL inputs following 1-h light pulses given during the early night in IGL-lesioned and sham-operated grass rats. Three patterns emerged: (1) IGL lesions had no effect on the Fos response to light, (2) IGL lesions resulted in a reversal in Fos responses to light, and (3) IGL lesions resulted in a lack of a Fos response to light. Of specific interest were the suprachiasmatic nucleus (SCN) and the olivary pretectal nucleus (OPT), both of which are retinorecipient and connect reciprocally with the IGL. Light-induced Fos expression in the SCN was unaffected by IGL lesions, whereas the OPT exhibited a significant reduction in Fos expression following a light pulse in animals with IGL lesions. Altogether, our results suggest that the OPT, but not the SCN, exhibits a reversal in Fos responses to light following IGL lesions that reverse masking responses in diurnal grass rats. Our results suggest that interconnections between the IGL and downstream brain areas (e.g., OPT) may play a role in determining the direction of the behavioral response to light.

Lesions of the Intergeniculate Leaflet Lead to a Reorganization in Circadian Regulation and a Reversal in Masking Responses to Photic Stimuli in the Nile Grass Rat

Light influences the daily patterning of behavior by entraining circadian rhythms and through its acute effects on activity levels (masking). Mechanisms of entrainment are quite similar across species, but masking can be very different. Specifically, in diurnal species, light generally increases locomotor activity (positive masking), and in nocturnal ones, it generally suppresses it (negative masking). The intergeniculate leaflet (IGL), a subdivision of the lateral geniculate complex, receives direct retinal input and is reciprocally connected with the primary circadian clock, the suprachiasmatic nucleus (SCN). Here, we evaluated the influence of the IGL on masking and the circadian system in a diurnal rodent, the Nile grass rat (Arvicanthis niloticus), by determining the effects of bilateral IGL lesions on general activity under different lighting conditions. To examine masking responses, light or dark pulses were delivered in the dark or light phase, respectively. Light pulses at Zeitgeber time (ZT) 14 increased activity in control animals but decreased it in animals with IGL lesions. Dark pulses had no effect on controls, but significantly increased activity in lesioned animals at ZT0. Lesions also significantly increased activity, primarily during the dark phase of a 12:12 light/dark cycle, and during the subjective night when animals were kept in constant conditions. Taken together, our results suggest that the IGL plays a vital role in the maintenance of both the species-typical masking responses to light, and the circadian contribution to diurnality in grass rats.

Dim nighttime illumination alters photoperiodic responses of hamsters through the intergeniculate leaflet and other photic pathways

In mammals, light entrains the central pacemaker within the suprachiasmatic nucleus (SCN) through both a direct neuronal projection from the retina and an indirect projection from the intergeniculate leaflet (IGL) of the thalamus. Although light comparable in intensity to moonlight is minimally effective at resetting the phase of the circadian clock, dimly lit and completely dark nights are nevertheless perceived differentially by the circadian system, even when nighttime illumination is below putative thresholds for phase resetting. Under a variety of experimental paradigms, dim nighttime illumination exerts effects that may be characterized as enhancing the plasticity of circadian entrainment. For example, relative to completely dark nights, dimly lit nights accelerate development of photoperiodic responses of Siberian hamsters transferred from summer to winter day lengths. Here we assess the neural pathways underlying this response by testing whether IGL lesions eliminate the effects of dim nighttime illumination under short day lengths. Consistent with previous work, dimly lit nights facilitated the expansion of activity duration under short day lengths. Ablation of the IGL, moreover, did not influence photoperiodic responses in animals held under completely dark nights. However, among animals that were provided dimly lit nights, IGL lesions prevented the short-day typical expansion of activity duration as well as the seasonally appropriate gonadal regression and reduction in body weight. Thus, the present data indicate that the IGL plays a central role in mediating the facilitative effects of dim nighttime illumination under short day lengths, but in the absence of the IGL, dim light at night influences photoperiodic responses through residual photic pathways.

The Intergeniculate Leaflet, but Not the Visual Midbrain, Mediates Hamster Circadian Rhythm Response to Constant Light

Several studies have demonstrated a variety of effects of intergeniculate leaflet (IGL) lesions on circadian rhythm regulation. Recent studies have suggested the possibility that certain rhythm functions attributed to the IGL are actually controlled by retinorecipient midbrain nuclei or other brain areas connected to the IGL. The present investigations evaluated whether midbrain lesions previously shown to block the phasic actions of benzodiazepine would also reduce or eliminate the period-lengthening effect of constant light (LL), a function that has been attributed to the IGL. Experiment 1 established that the circadian period of controls lengthened by about 0.57 h when the animals were transferred from constant dark (DD) to LL, but the magnitude of change was attenuated by about 50% in animals with IGL lesions caused by the neurotoxin N-methyl-D-aspartate (NMDA). In experiment 2, controls were compared to groups receiving either NMDA lesions of the pretectum or tectum or knife cuts designed to sever connections between the IGL and more medial retinorecipient nuclei. As in experiment 1, there were no differences between groups with respect to circadian period in DD. However, unlike experiment 1, all groups lengthened period equally in LL (overall mean increase = 0.57 h). Thus, the effect of LL on circadian period appears to be a joint result of photic information arriving at the circadian clock directly from the retinohypothalamic tract and indirectly through the IGL via the geniculohypothalamic tract, without involvement of visual midbrain. The results may have implications for the anatomical basis of Aschoff's rule.

Effects of intergeniculate leaflet lesions on circadian rhythms in the mouse

We investigated effects of bilateral electrolytic intergeniculate leaflet (IGL) lesions (IGLX) on circadian rhythms of the wheel-running activity in mice kept under constant darkness conditions (DD). As a result of complete bilateral IGL lesions, the period of a free-running rhythm was lengthened by ca. 45 min in comparison with a pre-operational one. The present findings confirm results obtained previously with other animals. However, for the first time locomotor activity levels were precisely assessed in mice (the number of wheel revolutions/day) before and after IGL lesions. A computer analysis of data showed a considerable decrease in that activity (by 68% on an average) in mice with complete bilateral IGL lesions in comparison with IGL-non-lesioned individuals. The obtained results show that also in mice IGL constitutes an anatomically important element of the mechanism of a circadian time-keeping system, which mediates the transfer of non-photic information to the suprachiasmatic nuclei (SCN) by modulating their activity.

Effects of intergeniculate leaflet lesions on circadian rhythms in Octodon degus

The intergeniculate leaflet (IGL) modulates photic and nonphotic entrainment of circadian rhythms in nocturnal species, but nothing is known about its role in diurnal species. We investigated the significance of the IGL for circadian rhythm function in the diurnal rodent, Octodon degus, by determining the effects of bilateral electrolytic IGL lesions (IGL X) on: (i) photic entrainment; (ii) reentrainment rates to photic cues following a 6-h phase advance of the light–dark (LD) cycle; (iii) reentrainment rates to nonphotic social and photic cues following a 6-h phase advance of the LD cycle; and (iv) the circadian period ( τ) of the activity rhythm in constant darkness (DD). IGL X significantly lengthened the duration ( α) of the entrained activity rhythm and produced a significantly earlier phase of activity onset under entrained (LD 12:12) conditions, but did not change phase of activity offset, rhythm amplitude or mean daily activity levels. IGL X failed to modify τ of free-running activity rhythms in DD or alter reentrainment rates of circadian rhythms to nonphotic social and photic cues or photic cues alone. Thus, the IGL modulates two parameters of photic entrainment, but is not necessary for reentrainment to either nonphotic social or photic cues. Our results contribute to the growing comparative database on the neural mechanisms controlling circadian rhythms and indicate that the role of the IGL varies across species with no apparent relationship between diurnality–nocturnality and circadian function.

Enhanced masking response to light in hamsters with IGL lesions.

Syrian hamsters with intergeniculate leaflet or sham lesions were given tests with a series of light pulses of gradually decreasing intensities. The light pulses were given early in the night, at zeitgeber time 14-15. The amount of wheel running during the pulses was compared to that in the same hour on a night with no light pulses. Hamsters with intergeniculate leaflet lesions showed a significantly greater suppression of their wheel running in response to light than the sham-lesioned animals. The lesioned animals also had larger negative phase angles of entrainment to the 14:10-h light-dark cycle than sham-operated controls. However, phase shifting in response to light pulses at either zeitgeber time 14 or 18 was not significantly altered by the lesions. Preferences for spending more time in a dark than a light area were not abolished by the lesions. It is concluded that the intergeniculate leaflet in the Syrian hamster cannot be of paramount importance for masking of locomotor activity by light but may play a modulating role.

The intergeniculate leaflet does not mediate the disruptive effects of constant light on circadian rhythms in the rat

Prolonged constant light exposure causes disruptions in circadian rhythms, resulting in splitting of circadian activity rhythms in hamsters and arrhythmicity in rats. Hamsters with lesions of the thalamic intergeniculate leaflet do not exhibit constant light-induced disruptions in rhythmicity. We have shown that circadian rhythms of rats with monosodium glutamate-induced neurotoxic damage to visual pathways persist under constant light, and hypothesized that monosodium glutamate damaged the retinogeniculate pathway, thus preventing constant light-induced arrhythmicity. The present study demonstrates, however, that the intergeniculate leaflet does not mediate these effects in rats. Rats with bilateral electrolytic intergeniculate leaflet lesions showed the same rate of disruption of circadian temperature rhythms as did sham-operated animals, housed under constant light. We also show that, unlike intergeniculate leaflet-lesioned rats, rats treated neonatally with monosodium glutamate exhibit neuropeptide Y fiber staining in the suprachiasmatic nucleus, indicating that the geniculohypothalamic tract is functionally intact following monosodium glutamate treatment. Taken together, these data demonstrate that the disruption of circadian rhythms during constant light exposure is not mediated directly via the geniculohypothalamic tract in rats. Whether this disruption in rhythmicity results from effects of constant light exposure on the circadian pacemaker, or is a direct effect of light on body temperature, is unknown. Retinal or collicular damage in monosodium glutamate-treated rats may render these animals insensitive to the disruptive effects of constant light.

The Role of the Intergeniculate Leaflet in Entrainment of Circadian Rhythms to a Skeleton Photoperiod

Mammalian circadian rhythms are synchronized to environmental light/dark (LD) cycles via daily phase resetting of the circadian clock in the suprachiasmatic nucleus (SCN). Photic information is transmitted to the SCN directly from the retina via the retinohypothalamic tract (RHT) and indirectly from the retinorecipient intergeniculate leaflet (IGL) via the geniculohypothalamic tract (GHT). The RHT is thought to be both necessary and sufficient for photic entrainment to standard laboratory light/dark cycles. An obligatory role for the IGL-GHT in photic entrainment has not been demonstrated. Here we show that the IGL is necessary for entrainment of circadian rhythms to a skeleton photoperiod (SPP), an ecologically relevant lighting schedule congruous with light sampling behavior in nocturnal rodents. Rats with bilateral electrolytic IGL lesions entrained normally to lighting cycles consisting of 12 hr of light followed by 12 hr of darkness, but exhibited free-running rhythms when housed under an SPP consisting of two 1 hr light pulses given at times corresponding to dusk and dawn. Despite IGL lesions and other damage to the visual system, the SCN displayed normal sensitivity to the entraining light, as assessed by light-induced Fos immunoreactivity. In addition, all IGL-lesioned, free-running rats showed masking of the body temperature rhythm during the SPP light pulses. These results show that the integrity of the IGL is necessary for entrainment of circadian rhythms to a lighting schedule like that experienced by nocturnal rodents in the natural environment.

Daily Wheel Running Activity Modifies the Period of Free-Running Rhythm in Rats Via Intergeniculate Leaflet

KURODA, H., M. FUKUSHIMA, M. NAKAI, T. KATAYAMA AND N. MURAKAMI. Daily wheel running activity modifies the period of free-running rhythm in rats via intergeniculate leaflet. PHYSIOL BEHAV 61(5) 633–637, 1997.—The period of free-running rhythms (tau) in rats, as measured using a running wheel, is different from that measured using an Automex. The aim of this work was to examine the effects of lesions of the intergeniculate leaflet (IGL) on the tau of these two activity rhythms. When blind rats were transferred from a cage with a running wheel to a cage without a running wheel, the tau lengthened. The tau of the wheel-running activity was associated with the number of wheel revolutions per day. A complete lesion of the IGL lengthened the tau of the wheel-running activity, and caused a reduction in the number of wheel revolutions per day in all rats. In rats housed in cages without a running wheel, locomotor activity was reduced by IGL lesions, although the tau was unaffected. When IGL-lesioned rats were transferred from a cage with a running wheel to a cage without a running wheel, no further change was observed. These results indicate that the tau is modified by the daily activity of wheel-running, but not by general locomotor activity, and that the IGL may be involved in this modification.

Lesions of the thalamic intergeniculate leafleet block activity-induced phase shifts in the circadian activity rhythm of the golden hamster

A variety of stimuli, which are associated with acute increases in locomotor activity, induce similar phase-dependent shifts in the circadian rhythm of locomotor activity in golden hamsters. Treatment with the benzodiazepine, triazolam (Tz), or transfer of an animal normally housed without a running wheel to a new cage with 1 h of access to a wheel are both examples of such stimuli. Phase shifts normally induced by injections of Tz can be blocked by lesions of the intergeniculate leaflet (IGL) of the thalamus. Experiments were conducted to determine whether phase shifts induced by transfer to a new cage with a running wheel also require an intact IGL. Animals normally housed without running wheels were transferred to new cages with access to wheels for 1 h a few hours before the expected onset of activity. They then received either lesions of the IGL or sham lesions and, after recovery, they were again transferred to new cages with running wheels for 1 h. Lesions of the IGL blocked phase shifts normally induced by wheel access while sham lesions had no effect. The amount of wheel-running and total locomotor activity which occurred during access to the running wheel were significantly reduced by IGL lesions. These results indicate that the phase-shifting effect of a novel running wheel depends upon an intact IGL.

Intergeniculate leaflet lesions and behaviorally-induced shifts of circadian rhythms

The aim of this work was to assess the effect of lesions of the intergeniculate leaflet on nonphotic phase shifts produced by confining hamsters to novel running wheels for 3 h in the middle of the subjective day. In intact hamsters this procedure produces large phase advances provided that the hamsters maintain high levels of wheel running during the confinement. Intergeniculate leaflet lesions blocked or reduced phase shifts after confinement to a novel wheel. However, for most animals these lesions also reduced both the amount of activity during the 3 h pulse in the novel wheel and the amount of daily wheel running in the home cage. To boost activity of lesioned hamsters to levels associated with large phase shifts, the animals were confined to novel wheels at low ambient temperature. The lesioned hamsters still failed to show large phase shifts. The benzodiazepine triazolam also failed to induce phase shifts in lesioned animals, but it induced less activity in lesioned animals as compared to sham-operated controls. The data support the hypothesis that the intergeniculate leaflet conveys information about nonphotic phase-shifting to the circadian pacemaker in the suprachiasmatic nucleus. They also raise the possibility that some effects of intergeniculate leaflet lesions previously interpreted as having a photic basis, might be due to the activity-lowering effect of the lesions.

Photoperiodic responsiveness of hamsters with lesions of the lateral geniculate nucleus is related to hippocampal damage

We tested the hypothesis that the geniculohypothalamic tract is important for hamster photoperiodism. Adult male hamsters, maintained in a long photoperiod (LD 14:10), received either large bilateral neurotoxic lesions of the lateral geniculate nucleus (LGN) or sham lesions. One week later, half of the animals from each group were transferred to a short photoperiod (LD 8:16) where they were maintained for 15 weeks. Most lesions effectively destroyed the intergeniculate leaflet (IGL) and much of the lateral geniculate complex. They also caused substantial damage to the overlying hippocampus. The lesions had no effect on long-day animals, but significantly reduced the extent of testicular regression during short photoperiod exposure. This effect, however, appeared to be the result of hippocampal, rather than geniculate, damage. Four individuals with complete IGL lesions, but minimal hippocampal damage, underwent a pattern of regression that was indistinguishable from controls. Body weight was increased by lesions in short-day, but not long-day, animals. This effect was not related to the extent of hippocampal damage. We conclude that geniculate input to the suprachiasmatic nuclei is not essential for hamster photoperiodism and that hippocampal damage may modify the effect of short daylengths on testes size.