Habenula lesions cause impaired cognitive performance in rats: implications for schizophrenia

Abstract

Cognitive impairment is a prominent feature of schizophrenia. Currently there is no well-accepted explanation of the aetiology of this disorder, but recent evidence indicates that dysfunction of the habenula may be involved. We therefore examined whether habenula lesions in Sprague-Dawley rats cause behavioural changes resembling those of schizophrenia. Rats received either habenula lesions, a sham operation or a small lesion of the overlying dorsal hippocampus as a check that effects observed were not due to incidental damage to this structure. As there are alterations of social behaviour, sensorimotor gating and cognition in schizophrenia, we examined comparable behaviours. Social interaction time was measured during a 5-min encounter with a novel juvenile conspecific. Prepulse inhibition of an acoustic startle response, as an index of sensorimotor gating, was measured with prepulses of various amplitudes, and spatial cognitive performance was assessed in the Morris water maze task. Histological analysis showed that habenula lesions substantially damaged both medial and lateral habenula bilaterally while largely sparing neighbouring structures. Assay of choline acetyltransferase (ChAT) in the interpeduncular nucleus terminal region of the habenulo-interpeduncular tract, showed marked reduction (by 80%) in habenula-lesioned animals. Habenula-lesioned rats, but not the control group with small dorsal hippocampus lesions, showed marked impairment of Morris maze performance compared to the sham-operated control group. Social interaction time and prepulse inhibition were not significantly altered in either lesion group. The results are consistent with a role of the habenula in cognition, and with the view that pathology of the habenula may contribute to the cognitive impairments of schizophrenia.

Bilateral Lesions of the Habenula Induce Attentional Disturbances in Rats

“…Recently, we began to examine this prediction by investigating the effects of habenula lesions on functions that are impaired in schizophrenia, namely memory performance, prepulse inhibition (PPI), and social interaction. Our results showed that habenula-lesioned rats exhibited a deficit in spatial learning in the Morris water maze, but no change of PPI or of social exploration, implicating habenula pathology particularly in memory impairment (Lecourtier et al, 2004).…”

“…Instead, the stimulus recesses themselves that have become associated with reward during training elicit an inappropriate level of responding. As only a slight, short-lasting increase of locomotor activity is present in habenula-lesioned animals (Lecourtier et al, 2004), it is unlikely that the increase of premature responding is merely a reflection of generalized hyperactivity. Moreover, it seems unlikely that the increased premature responding could be explained by a motor effect of the lesion to nonspecifically facilitate responding in the stimulus alcoves, since there was no increase at all of perseverative responding caused by the lesion.…”

“…The progressive deficit in choice accuracy is consistent with such a mechanism, but of course does not prove it. Further, we can reasonably eliminate the possibility that this lateoccurring impairment of choice accuracy arises from an impairment of visual ability, since in a different cognitive task, the Morris water-maze, rats with a lesion of the habenula performed the visible platform condition of the test as well as sham-operated controls, although they were impaired in finding the hidden platform (Lecourtier et al, 2004).…”

“…Lesions of the habenula or sham operations were performed as previously described (Lecourtier et al, 2004), except that inhalation anesthesia was used. The animals were anesthetized with isoflurane (Forene s , Abbott, USA) and placed in a stereotaxic frame with the tooth bar higher than the ear bars to correspond to the stereotaxic atlas of Pellegrino et al (1979).…”

“…Consistent with such widespread influences, it is implicated in diverse functions including anxiety (Murphy et al, 1996;Kurumaji et al, 2003), stress (Amat et al, 2001;Sica et al, 2000), analgesia (Cohen and Melzack, 1993), maternal behavior (Corodimas et al, 1993;Felton et al, 1998), sleep (Haun et al, 1992;Valjakka et al, 1998), behavioral flexibility (Thornton and Evans, 1982), reinforcement (Sutherland and Nakajima, 1981), and spatial memory (Lecourtier et al, 2004). The recent description of 15 subnuclei within the habenular complex (Andres et al, 1999;Geisler et al, 2003) should eventually be of great assistance for future research aimed at elucidating the particular circuits that mediate these specific behaviors.…”