Sensorimotor modulation of mood and depression: an integrative review.

Several lines of research on mood disorders reveal that depression involves a dysfunction in an affective fronto-limbic circuitry that involves the prefrontal cortices, the cingulate cortex, several limbic structures including the amygdala and the hippocampus, lower brainstem structures and the basal ganglia. In dealing with both depressive symptoms as well as their manifestation in the brain, clinical as well as basic research has emphasized mainly a top-down or central approach in elucidating the etiology of depression and its therapy. The present integrative review emphasizes the bottom-up or peripheral view of evaluating the impact of stimulation via sensory modalities or the motor system on the same circuitry in effecting mood regulation and possibly causing mood disorders, specifically depression. The paper shows that there is now a considerable accumulation of data from clinical observations as well as research with animal models to suggest that hypo- or hyper-activation of the sensory or the motor systems by manipulating visual, auditory, olfactory or gustatory inputs as well as physical exercise can have modulatory effects on mood and depressive symptoms. Moreover, depression in turn affects sensorimotor processing, resulting in an interaction that may further contribute to the aggravation of depressive symptoms. The paper also cites evidence that activation of the affective circuitry by central manipulations such as by means of deep brain stimulation has similar modulatory effects as peripheral stimulation on mood and depression. Finally, it is proposed that systematic investigations using animal models of depression on the impact of uni- or multisensory manipulation as well as of physical exercise may provide new insights into the etiology and treatment of depression in humans.

Blue but not red light stimulation in the dark has antidepressant effect in behavioral despair.

The present study investigated potential antidepressant effect of light exposure in the dark phase of a 12:12 L/D cycle on behavioral despair. In Exp.1, male Wistar rats were administered a single, 10 min broadband light pulse (1300lx) either 3h (ZT15) or 9h (ZT21) after dark onset (ZT12) and tested in two consecutive swim tests separated by 24 h. Photic stimulation at ZT21 but not ZT15 significantly reduced immobility in the second swim test relative to the first test compared to controls that were treated similarly except for light pulse administration (p<0.05). In Exp.2, groups were exposed to a single 10-min light pulse (1300lx) either in the blue or red end of the spectrum at ZT21 or were treated similarly except for photic exposure (controls). Exposure to blue light resulted in significantly reduced duration of immobility in the second swim test relative to that of the first test compared to the red light and control groups (p<0.05). The present findings suggest a critical role in the antidepressant effect of blue light stimulation for the melanopsin-containing ganglion cells in the retina that are sensitive to wavelengths in the blue but not red end of the visible spectrum.

Behavioral despair is differentially affected by the length and timing of photic stimulation in the dark phase of an L/D cycle.

The effect of varying the length and timing of photic stimulation in the dark phase of an L/D lighting cycle on behavioral despair was investigated in female Wistar rats. Animals were kept in a vivarium on an L/D 12 h:12 h light cycle (lights on at 0700 h) except for a single day of light exposure in an insulated chamber in the dark phase of the L/D schedule. Light pulses provided by an incandescent lamp (15- and 25-W, for Exps. 1 and 2, respectively) either 2-h (Exp. 1) or 30-min in length (Exp. 2) were administered to independent groups of rats (n=8 each) either in the early, middle or late hours of the dark phase of the L/D cycle in the insulated chamber. Light pulses were delivered beginning 2 1/2, 5 1/2 or 7 1/2 h (Exp. 1) or 3 1/4, 6 1/4 and 8 1/4 h (Exp. 2) after dark onset. Control animals were treated similarly except for photic stimulation. In each experiment, an additional group received a light pulse of the appropriate length both in the early and late portion of the dark phase (double double-pulse groups): beginning 2 1/2 and 7 1/2 h (Exp. 1) or 3 1/4 and 8 1/4 h (Exp. 2) after dark onset. All animals then underwent two forced swim tests separated by 24 h with the first test occurring in the light (starting at 1500 h) following the dark phase when photic stimulation was administered. Total duration of immobility in the second swim test was measured to gauge behavioral despair. In Exp. 1, the 2-h double double-pulse group showed significantly shorter immobility compared to controls (p<0.05). In Exp. 2, 30-min light pulse delivered late in the dark phase reduced immobility significantly compared to controls and all the other light-treated groups (p<0.01). Results indicate that photic stimulation may have antidepressant effect on behavioral despair depending on the timing and the duration of photic stimulation.

Seasonal variability in behavioral despair in female rats.

Separate groups of female Wistar rats were tested every three months over a year to assess the extent of seasonal variability in the behavioral despair model of depression consisting of 2 swim tests separated by 24 h. There was a significant seasonal variability in the duration of immobility in the swim tests; duration of immobility was shorter in August and November than in February and May. These findings suggest reduced immobility and susceptibility to behavioral despair in summer and fall compared to winter and spring.

Prolonged effect of an anesthetic dose of ketamine on behavioral despair.

The present study investigated the effect of a single, anesthetic dose of ketamine, a noncompetitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, on behavioral despair, an animal model of depression. Separate groups of male Wistar rats injected with an anesthetic dose of ketamine (160 mg/kg ip) and tested 3, 7, or 10 days later showed significantly less immobility in the second of two forced-swim tests compared to saline-injected controls. Ketamine- and saline-treated animals did not differ significantly in the swim tests with respect to other behavioral measures, namely diving, jumping, and head shakes. The present findings point to an ameliorative effect of ketamine on behavioral despair and support the view that NMDA antagonists may have a beneficial effect on depression.

Er:YAG laser ablation of cerebellar and cerebral tissue.

With the availability of suitable fibres, the Er:YAG laser has become an indispensable tool for invasive neurosurgical applications as a source of precise ablation. The aim of this study was to investigate the ablative effects of the Er:YAG laser on brain tissue. The response of neuronal tissue to 2.94 microns Er:YAG laser irradiation was investigated on excised rat brain specimens. Ablation craters were created in cerebral and cerebellar tissues using 0.3, 0.5 and 1.0 J single pulses of 150 microseconds duration. The corresponding average irradiances were 37.7 J/cm2, 62.9 J/cm2 and 125.8 J/cm2, respectively. Craters were checked qualitatively, crater dimensions were measured and compared, and volume of ablated tissue was estimated. Laser-induced crater dimensions were found to be significantly different at different energy levels applied. Moreover, dimensions of craters on cerebral and cerebellar tissues were significantly different in terms of dimensions. We observed that with the Er:YAG laser ablation craters were created with practically no thermal damage to adjacent tissues. The differences observed in the response of cerebral and cerebellar cortical tissues were dependent on the anatomical and chemical differences.

Lesion of the bed nucleus of the stria terminalis enhances learned despair.

The bed nucleus of the stria terminalis (BNST) was lesioned in adult male Wistar rats (n = 9) and its involvement in coping behavior during forced swim stress examined. Rats remain immobile longer in the second of two swim tests, a phenomenon known as learned despair. Results revealed that, compared to sham-operated controls (n = 8), BNST-lesioned animals displayed immobility significantly earlier and for longer durations in the second swim test. Rats with BNST lesions also showed significantly reduced escape behavior in the form of fewer numbers of jumps and dives compared to controls. Mobility deficits were not due to general motor impairment as revealed by an open field test. Results suggest that the BNST may modulate coping behavior especially during uncontrollable stress.

Neither triazolam nor activity phase advance circadian locomotor activity in SCN-lesioned hamsters bearing fetal SCN transplants.

Both triazolam (Tz) and exercise can phase advance free-running locomotor activity rhythms in intact hamsters. Furthermore, Tz increases activity at the time of injection, and this appears to be the mechanism whereby Tz produces phase shifts. This study tested the phase-shifting effect of Tz in SCN-lesioned (SCN-X) hamsters that had regained circadian rhythms of locomotor activity after transplantation of fetal SCN into the third ventricle. The results indicate that in both groups, increases in locomotor activity are seen at the time of Tz injection, and most intact animals, but no grafted animals show a phase advance in response to Tz administration. Given that hamsters bearing SCN grafts have limited neural connections between the host brain and transplanted SCN tissue, the results suggest that a site outside the SCN, with afferents to these nuclei, mediates the phase-shifting effect of Tz and of exercise.

Tracing SCN graft efferents with Dil.

The suprachiasmatic nuclei (SCN) regulate circadian rhythmicity in many biological and behavioral responses. Hamsters are made permanently arrhythmic by bilateral destruction of the SCN. Circadian locomotor rhythmicity is restored by fetal tissue transplants placed in the 3rd ventricle (3V). If intact animals are implanted with fetal SCN grafts, they maintain locomotor activity rhythms when the host SCN are subsequently destroyed. The mechanism(s) whereby the SCN (either grafted or in situ) regulate locomotor rhythmicity is not known. Evidence from other graft models point to the possibility of efferents to appropriate targets in the host. In the present study, efferent connections of transplanted fetal SCN were examined using the carbocyanine dye, Dil. Intact or SCN-lesioned animals were sacrificed 7 or 40 days after receiving fetal SCN grafts into 3V. Dil crystals were placed on the grafts in fixed brains which were then incubated for 3-6 weeks before sectioning. Sections bearing Dil-labelled efferents from the graft were photographed and then stained for immunoreactive VIP and NP cells to locate donor SCN. Although labelled efferents were observed in a majority of the grafts, most were confined to the limits of the graft. The few labelled efferents that entered the host tissue when the graft seemed to merge with the host did not extend very far regardless of whether the graft contained immunohistochemical evidence for donor SCN or not. The observation of limited graft-host connectivity suggests either that a limited number of efferents is sufficient to support circadian locomotor rhythmicity, or that the mechanism mediating restoration of function entails a diffusible substance.

The role of jejunal signals in the long-term regulation of food intake in the rat.

The significance of the upper small intestine in long-term regulation of food intake was investigated in pairs of parabiotic rats in which a 30 cm transected segment of each rat's intestine was sewn into continuity with the intestine of its partner. In this preparation, food eaten by one rat passes through its own stomach and 5 cm of its duodenum and then moves into the partner's intestine. The food traverses the 30 cm segment of the partner's intestine before returning to its own lower small intestine. All pairs were fed a liquid diet 11 hr/day. When the regular diet was diluted 1:1 with water, all rats showed a significant, nearly compensatory increase in their daily intake. In contrast, when only one rat in each pair was fed, thereby depriving it of intrajejunal input from its fasted partner, there was no significant increase in its food intake for about six days, followed by a gradual increase which was never fully compensatory as shown by continued loss of weight for the pair. Feeding rats could not be trained to notice the loss of intrajejunal input by making such loss coincident with a change in diet flavor. Jejunal satiety cues arising from a 30 cm segment, if they exist, do not seem to play a significant role in long-term regulation of food intake.

Comparison of gastric, duodenal and jejunal contributions to the inhibition of food intake in the rat.

Rats equipped with tubes leading to their stomach, duodenum or jejunum were infused with a liquid diet for 9 hr (4 ml/hr) and were allowed to eat during the last 8 hr of infusion. All rats ate significantly less on diet infusion days than on saline or no infusion days. A second study showed that a taste aversion could not be conditioned to flavored water associated with diet infusion. Apparently, intrajejunal injection of nutrients produces satiety and not discomfort. Infusion of the diet for 5 consecutive days into the stomach, duodenum or jejunum consistently and significantly lowered food intake by reducing meal size, not meal frequency. Results suggest that the small intestine below the infusion site contributes to normal satiety.