Research ReportLesions of the habenula produce stress- and dopamine-dependent alterations in prepulse inhibition and locomotion
Introduction
The habenula complex, a paired midline structure just medial to the thalamus, provides a neural pathway that mediates forebrain control over midbrain dopaminergic and serotonergic firing (Sutherland, 1982, Andres et al., 1999). The habenula receives convergent input from most limbic brain regions including the hypothalamus, central amygdala, substantia innominata, diagonal band of Broca, nucleus accumbens, septum, and prefrontal cortical regions (Sutherland, 1982, Ellison, 2002). In addition to receiving afferent input from brainstem dopamine and serotonergic systems, it is a principle regulator of firing of the ventral tegmental area (VTA), dorsal raphe nucleus (DRN), and interpeduncular nucleus (IP) (Wang and Aghajanian, 1977, Reisine et al., 1982, Skagerberg et al., 1984, Nishikawa et al., 1986, Varga et al., 2003).
Given the anatomical and functional ability of the habenula to regulate dopaminergic and serotonergic transmission, it is plausible that habenula dysfunction may disrupt the regulation of behavior influenced by monoamine transmission. Past studies have indeed shown that lesions of the habenula lead to alterations in the normal regulation of noradrenergic, dopaminergic, and serotonergic transmission (Lisoprawski et al., 1980, Nishikawa et al., 1986, Murray et al., 1994, Murphy et al., 1996, Amat et al., 2001). However, the consequences of habenula damage on cognitive and motor behaviors have been mixed. Several laboratories have demonstrated lesioned-induced impairment in a number of behaviors including avoidance learning (Thornton et al., 1994), water maze performance (Thornton and Davies, 1991, Lecourtier et al., 2004), and locomotive activity (Lee and Huang, 1988, Thornton et al., 1990, Murphy et al., 1996). On the other hand, other studies have found little influence of habenula damage on such behaviors (Thornton et al., 1994, Vale-Martinez et al., 1997).
At present, the variables which contribute to these differential outcomes are presently ill-defined; however, some evidence indicates that the functional consequences of habenula damage appear most apparent in lesioned animals which have been exposed to various types of stressors. For example, Thornton and Bradbury (1989) found that habenula lesions impair one-way avoidance learning only when physical effort or stress levels are increased. The addition of isolation and food deprivation stress also alters normal elevated plus-maze behavior in lesioned animals (Murphy et al., 1996). Furthermore, Maier and colleagues (Amat et al., 2001) have shown that an intact habenula is essential for subsequent long-term alterations in neural and behavioral responses after uncontrollable stress. Together, these results suggest that the habenula may play a more active and central role in the long-term modification of monoamine transmission and behavioral responses subsequent to aversive and stressful events. Electrophysiological and c-fos immunoreactivity studies in rodents have indeed demonstrated that the habenula is activated in response to various aversive stressors, including stimulation of the tail, restraint, novel environments, and footshock (Benabid and Jeaugey, 1989, Wirtshafter et al., 1994, Gao et al., 1996, Smith et al., 1997). We have previously reported that the habenula also showed increased expression of synaptic plasticity genes associated with long-term changes in neuronal activity in response to stress associated with fear conditioning (Ressler et al., 2002). Along with evidence indicating the habenula's role in regulating monoamine transmission, these results suggest that stress may induce long-term structural changes in the habenula which influences subsequent monoamine-dependent behaviors.
In the current study, we investigated the effects of habenula lesions on the acquisition and expression of conditioned fear and whether lesions altered behavioral measures of dopamine sensitivity and sensorimotor gating after stress associated with conditioned fear. Our results demonstrate that despite the correlational evidence of increased activity with conditioned fear, the habenula does not appear to be essential for the acquisition or expression of this form of learning. However, habenula lesions do lead to stress-dependent changes in behavioral measures of dopamine sensitivity as measured with apomorphine, a D1/D2 agonist. Sensorimotor gating deficits were also found that were reversible with clozapine, an atypical antipsychotic with mixed dopamine/serotonin antagonist properties. These data provide evidence for a role of the habenula complex in long-term stress-dependent modulation of monoamine systems and associated behaviors. These data also suggest that abnormalities in this regulatory system produce changes in measures of sensorimotor gating and dopamine sensitivity in animals.
Section snippets
Postsurgery PPI and fear conditioning
Two days after matching, animals received either discrete lesions restricted to the habenula complex or sham lesions (Fig. 1a). Of the 22 habenula-lesioned animals, 1 died after surgery and 3 had only unilateral habenula damage. Thus, 20 sham-lesioned and 18 habenula-lesioned animals were included in analysis. Damage to the habenula extended the rostrocaudal boundaries in most mice. In some mice, sparing was observed in the rostral (n = 4) or caudal (n = 4) pole of the habenula complex. In most
Discussion
Our findings indicate that lesions of the habenula do not result in immediate behavioral deficits. Groups of animals matched with comparable PPI levels before surgery demonstrated similar PPI performance either 1 or 2 weeks after surgery, regardless of lesion type. Likewise, no differences were seen in reactivity to shock or the acquisition and retention of conditioned fear. Following conditioned fear, habenula-lesioned animals displayed significantly less PPI than control-lesioned animals.
Animals and experimental design
Male C57BL/6J mice, 4 to 9 weeks of age and weighing 20–30 g, were obtained from Jackson Labs (Bar Harbor, ME) and used as subjects. Mice were kept in groups of five to six in plastic cages (30 × 20 × 16 cm) on corn dust bedding. They were housed at 24 °C with a 12/12-h light/dark cycle with ad libitum access to food and water. All experiments were conducted on mice between 5 and 10 weeks of age. The experiments were approved by our Institutional Protocol Approval Committee and were in
Acknowledgments
This work was funded by NIH (MH069884, MH073389), Yerkes National Primate Research Center, the Center for Behavioral Neuroscience (NSF IBN-987675), and, in part, by the NIH base grant to the Yerkes NPRC (RR00165).
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