Lesions of the habenula produce stress- and dopamine-dependent alterations in prepulse inhibition and locomotion - PubMed (original) (raw)

Comparative Study

Lesions of the habenula produce stress- and dopamine-dependent alterations in prepulse inhibition and locomotion

Scott A Heldt et al. Brain Res. 2006.

Abstract

The habenula complex modulates the activity of dopamine and serotonin systems in the brain. An important question remains whether there is a link between habenula dysfunction and monoamine-related disorders, such as schizophrenia. In this study, we describe an interaction between habenula lesions and stress that produces long-lasting effects on behavior. Mice received control lesions or bilateral electrolytic lesions of the habenula and were tested for fear-potentiated startle and freezing measures of conditioned fear. They were also tested for prepulse inhibition (PPI) and locomotor activity in the presence or absence of a dopaminergic agonist (apomorphine) or an atypical antipsychotic with mixed dopamine/serotonin antagonist properties (clozapine). There were no detectable effects of habenula lesions on fear conditioning and no effects on PPI in the absence of stress. However, following conditioned fear stress, habenula-lesioned animals showed decreased PPI which normalized with clozapine. Lesioned animals also showed diminished activity at baseline, with hyperlocomotion following apomorphine. These data support the hypothesis that the habenula may be normally involved in stress-dependent regulation of monoamine systems.

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Figures

Fig. 1

Fig. 1

(a) Representative photomicrographs of sham-lesioned animals (top row) and habenula-lesioned animals (bottom row). Arrows demonstrate location of habenula in control and lesioned animals. (b) Serial histological reconstruction of electrolytic lesions of the habenula in mice included in study. Reconstructions have been transcribed onto modified plates 40, 41, 43, 45, 47, and 49 as adapted from Paxinos and Franklin (2001) and illustrate the largest (light grey) and smallest (dark grey) lesions included in statistical analyses.

Fig. 2

Fig. 2

(a) Pre- and postsurgery PPI sessions designed to examine the effects of habenula damage on PPI. Mean percent PPI scores represent the average inhibition computed over 4 prepulse intensities (2, 4, 8, or 10 dB above a 63 dB white noise background). Postsurgery test was performed 1 week after surgery. (b) Freezing response to the presence of the tone conditioned stimulus (CS) during acquisition of conditioned fear. Training consisted of 5 tone + shock trials on each of 3 consecutive days (15 total trials). (c) Mean reactivity score in response to the 0.4 mA footshock used as the unconditioned stimulus (US) during fear conditioning. (d–e) Retention of conditioned fear as measured by (d) fear-potentiated startle and (e) freezing. The retention test was conducted 24 h after last training session. Bars represent means + SEM.

Fig. 3

Fig. 3

(a) Pre- and poststress PPI sessions designed to examine the effects of habenula damage and conditioned fear stress on PPI. Mean percent PPI scores represent the average inhibition computed over 4 prepulse intensities (2, 4, 8, or 10 dB). Poststress session was conducted 1 week after prestress session (2 week after surgery) during which time animals were given fear conditioning. (b) Mean percent PPI scores at each of the prepulse intensities. (c) Effects of clozapine on PPI in habenula- and sham-lesioned mice. Bars depict the mean percent PPI computed over 4 prepulse intensities. Mice were given i.p. injections of either vehicle or clozapine (6 mg/kg) 30 min before behavioral testing using a random crossover experimental design. (d) The effects of apomorphine on motor activity in habenula- and sham-lesioned animals. Bars represent mean increases in motor activity in response to apomorphine. The mean was computed by subtracting the number of compartment entries on session 1 (no drug, shams: M = 34.5, MSE = 3.7; habenula: M = 17.5, MSE = 2.3) from number of compartment entries on session 2 (apomorphine, shams: M = 87.3, MSE = 6.7; habenula: M = 104.5, MSE = 7.5). Apomorphine (2 mg/kg) was administered 30 min before session 2. Bars represent means + SEM (*_P_s < 0.05).

Fig. 4

Fig. 4

(a) Mean percent PPI scores pre- and poststress for habenula, geniculate (control), and sham-lesioned animals. Poststress session was conducted 1 week after prestress session (2 week after surgery) during which time animals were given fear conditioning. Mean percent PPI scores represent the average inhibition averaged computed over 4 prepulse intensities (2, 4, 8, or 10 dB). (b–c) Comparison of mean percent PPI scores for Groups 1 and 2. Animals in Group 1 received stress between weeks 1 and 2 after lesion surgery. Group 2 animals that received stress between weeks 2 and 3 postsurgery (*P < 0.05).

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