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Basal forebrain projections to the lateral habenula modulate aggression reward

View Article: PubMed Central - PubMed

ABSTRACT

Maladaptive aggressive behavior is associated with a number of neuropsychiatric disorders1 and is thought to partly result from inappropriate activation of brain reward systems in response to aggressive or violent social stimuli2. Nuclei within the ventromedial hypothalamus3–5, extended amygdala6 and limbic7 circuits are known to encode initiation of aggression; however, little is known about the neural mechanisms that directly modulate the motivational component of aggressive behavior8. To address this, we established a mouse model to measure the valence of aggressive inter-male social interaction with a smaller subordinate intruder as reinforcement for the development of conditioned place preference (CPP). Aggressors (AGG) develop a CPP, while non-aggressors (NON) develop a conditioned place aversion (CPA), to the intruder-paired context. Further, we identify a functional GABAergic projection from the basal forebrain (BF) to the lateral habenula (lHb) that bi-directionally controls the valence of aggressive interactions. Circuit-specific silencing of GABAergic BF-lHb terminals of AGG with halorhodopsin (NpHR3.0) increases lHb neuronal firing and abolishes CPP to the intruder-paired context. Activation of GABAergic BF-lHb terminals of NON with channelrhodopsin (ChR2) decreases lHb neuronal firing and promotes CPP to the intruder-paired context. Lastly, we show that altering inhibitory transmission at BF-lHb terminals does not control the initiation of aggressive behavior. These results demonstrate that the BF-lHb circuit plays a critical role in regulating the valence of inter-male aggressive behavior and provide novel mechanistic insight into the neural circuits modulating aggression reward processing.

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BF-lHb activity bi-directionally modulates aggression rewardSchematic of (a) optogenetic viral infection strategy and (b) aggression CPP procedure. Representative CPP heatmaps for eYFPBF→lHb, ChR2BF→lHb and NpHR3BF→lHb between (c) NON and (f) AGG mice. (d) Normalized (F2,26 = 5.019, one-way ANOVA P < 0.05; post hoc test, *P < 0.05, n = 9–10/group) and subtracted CPP score (F2,26 = 6.666, one-way ANOVA P < 0.01; post hoc test, *P < 0.05, n = 9–10/group) in NON::eYFPBF→lHb, NON::ChR2BF→lHb and NON::NpHr3BF→lHb. (e) Individual duration in intruder-paired context for NON::eYFPBF→lHb mice (t9 = 0.9129, P > 0.05; two-tailed paired t-test, n = 10/group), NON::ChR2BF→lHb mice (t8 = 2.362, *P < 0.05; two-tailed paired t-test, n = 9/group), and NON::NpHRBF→lHb mice (t9 = 2.344, *P < 0.05; two-tailed paired t-test, n = 10/group) during the Pretest and Test sessions. (g) Normalized (F2,20 = 5.470, one-way ANOVA P < 0.05; post hoc test, *P < 0.05, n = 7–8/group) and subtracted CPP score (F2,20 = 4.964, one-way ANOVA P < 0.05; post hoc test, *P < 0.05, n = 7–8/group) for intruder-paired context in AGG::eYFPBF→lHb, AGG::ChR2BF→lHb and AGG::NpHr3BF→lHb. (h) Individual duration in intruder-paired context for AGG::eYFPBF→lHb mice (t6 = 5.070, **P < 0.01; two-tailed paired t-test, n = 7/group), AGG::ChR2BF→lHb mice (t7 = 2.394, *P < 0.05; two-tailed paired t-test, n = 8/group), and AGG::NpHRBF→lHb mice (t7 = 1.763, P > 0.05; two-tailed paired t-test, n = 8/group). Summary data are represented as mean ± s.e.m. NON, non-aggressor; AGG, aggressor; lHb, lateral habenula; BF, basal forebrain; n.c., no change.
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Figure 3: BF-lHb activity bi-directionally modulates aggression rewardSchematic of (a) optogenetic viral infection strategy and (b) aggression CPP procedure. Representative CPP heatmaps for eYFPBF→lHb, ChR2BF→lHb and NpHR3BF→lHb between (c) NON and (f) AGG mice. (d) Normalized (F2,26 = 5.019, one-way ANOVA P < 0.05; post hoc test, *P < 0.05, n = 9–10/group) and subtracted CPP score (F2,26 = 6.666, one-way ANOVA P < 0.01; post hoc test, *P < 0.05, n = 9–10/group) in NON::eYFPBF→lHb, NON::ChR2BF→lHb and NON::NpHr3BF→lHb. (e) Individual duration in intruder-paired context for NON::eYFPBF→lHb mice (t9 = 0.9129, P > 0.05; two-tailed paired t-test, n = 10/group), NON::ChR2BF→lHb mice (t8 = 2.362, *P < 0.05; two-tailed paired t-test, n = 9/group), and NON::NpHRBF→lHb mice (t9 = 2.344, *P < 0.05; two-tailed paired t-test, n = 10/group) during the Pretest and Test sessions. (g) Normalized (F2,20 = 5.470, one-way ANOVA P < 0.05; post hoc test, *P < 0.05, n = 7–8/group) and subtracted CPP score (F2,20 = 4.964, one-way ANOVA P < 0.05; post hoc test, *P < 0.05, n = 7–8/group) for intruder-paired context in AGG::eYFPBF→lHb, AGG::ChR2BF→lHb and AGG::NpHr3BF→lHb. (h) Individual duration in intruder-paired context for AGG::eYFPBF→lHb mice (t6 = 5.070, **P < 0.01; two-tailed paired t-test, n = 7/group), AGG::ChR2BF→lHb mice (t7 = 2.394, *P < 0.05; two-tailed paired t-test, n = 8/group), and AGG::NpHRBF→lHb mice (t7 = 1.763, P > 0.05; two-tailed paired t-test, n = 8/group). Summary data are represented as mean ± s.e.m. NON, non-aggressor; AGG, aggressor; lHb, lateral habenula; BF, basal forebrain; n.c., no change.

Mentions: To investigate the functional consequences of BF-lHb neuronal firing on aggression reward, we paired photostimulation of ChR2BF→lHb and NpHR3BF→lHb in AGG and NON during the CPP test (Fig. 3a–b). NON::ChR2BF→lHb stimulation promoted CPP (Fig. 3c–e), mimicking responses observed in control AGG. Conversely, AGG::NpHR3BF→lHb stimulation induced CPA (Fig. 3f–h), mimicking responses observed in control NON. Neither NON::NpHR3BF→lHb or AGG::ChR2BF→lHb stimulation significantly affected the expression of CPP or CPA. Viral expression (Extended Data Figure 6a–f) and locomotor activity (Extended Data Figure 6g–j) was not different between conditions. These data confirm that BF-lHb circuitry modulates the rewarding component of aggressive behavior and is both necessary and sufficient for the expression of CPP in AGG and CPA in NON.


Basal forebrain projections to the lateral habenula modulate aggression reward
BF-lHb activity bi-directionally modulates aggression rewardSchematic of (a) optogenetic viral infection strategy and (b) aggression CPP procedure. Representative CPP heatmaps for eYFPBF→lHb, ChR2BF→lHb and NpHR3BF→lHb between (c) NON and (f) AGG mice. (d) Normalized (F2,26 = 5.019, one-way ANOVA P < 0.05; post hoc test, *P < 0.05, n = 9–10/group) and subtracted CPP score (F2,26 = 6.666, one-way ANOVA P < 0.01; post hoc test, *P < 0.05, n = 9–10/group) in NON::eYFPBF→lHb, NON::ChR2BF→lHb and NON::NpHr3BF→lHb. (e) Individual duration in intruder-paired context for NON::eYFPBF→lHb mice (t9 = 0.9129, P > 0.05; two-tailed paired t-test, n = 10/group), NON::ChR2BF→lHb mice (t8 = 2.362, *P < 0.05; two-tailed paired t-test, n = 9/group), and NON::NpHRBF→lHb mice (t9 = 2.344, *P < 0.05; two-tailed paired t-test, n = 10/group) during the Pretest and Test sessions. (g) Normalized (F2,20 = 5.470, one-way ANOVA P < 0.05; post hoc test, *P < 0.05, n = 7–8/group) and subtracted CPP score (F2,20 = 4.964, one-way ANOVA P < 0.05; post hoc test, *P < 0.05, n = 7–8/group) for intruder-paired context in AGG::eYFPBF→lHb, AGG::ChR2BF→lHb and AGG::NpHr3BF→lHb. (h) Individual duration in intruder-paired context for AGG::eYFPBF→lHb mice (t6 = 5.070, **P < 0.01; two-tailed paired t-test, n = 7/group), AGG::ChR2BF→lHb mice (t7 = 2.394, *P < 0.05; two-tailed paired t-test, n = 8/group), and AGG::NpHRBF→lHb mice (t7 = 1.763, P > 0.05; two-tailed paired t-test, n = 8/group). Summary data are represented as mean ± s.e.m. NON, non-aggressor; AGG, aggressor; lHb, lateral habenula; BF, basal forebrain; n.c., no change.
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Figure 3: BF-lHb activity bi-directionally modulates aggression rewardSchematic of (a) optogenetic viral infection strategy and (b) aggression CPP procedure. Representative CPP heatmaps for eYFPBF→lHb, ChR2BF→lHb and NpHR3BF→lHb between (c) NON and (f) AGG mice. (d) Normalized (F2,26 = 5.019, one-way ANOVA P < 0.05; post hoc test, *P < 0.05, n = 9–10/group) and subtracted CPP score (F2,26 = 6.666, one-way ANOVA P < 0.01; post hoc test, *P < 0.05, n = 9–10/group) in NON::eYFPBF→lHb, NON::ChR2BF→lHb and NON::NpHr3BF→lHb. (e) Individual duration in intruder-paired context for NON::eYFPBF→lHb mice (t9 = 0.9129, P > 0.05; two-tailed paired t-test, n = 10/group), NON::ChR2BF→lHb mice (t8 = 2.362, *P < 0.05; two-tailed paired t-test, n = 9/group), and NON::NpHRBF→lHb mice (t9 = 2.344, *P < 0.05; two-tailed paired t-test, n = 10/group) during the Pretest and Test sessions. (g) Normalized (F2,20 = 5.470, one-way ANOVA P < 0.05; post hoc test, *P < 0.05, n = 7–8/group) and subtracted CPP score (F2,20 = 4.964, one-way ANOVA P < 0.05; post hoc test, *P < 0.05, n = 7–8/group) for intruder-paired context in AGG::eYFPBF→lHb, AGG::ChR2BF→lHb and AGG::NpHr3BF→lHb. (h) Individual duration in intruder-paired context for AGG::eYFPBF→lHb mice (t6 = 5.070, **P < 0.01; two-tailed paired t-test, n = 7/group), AGG::ChR2BF→lHb mice (t7 = 2.394, *P < 0.05; two-tailed paired t-test, n = 8/group), and AGG::NpHRBF→lHb mice (t7 = 1.763, P > 0.05; two-tailed paired t-test, n = 8/group). Summary data are represented as mean ± s.e.m. NON, non-aggressor; AGG, aggressor; lHb, lateral habenula; BF, basal forebrain; n.c., no change.
Mentions: To investigate the functional consequences of BF-lHb neuronal firing on aggression reward, we paired photostimulation of ChR2BF→lHb and NpHR3BF→lHb in AGG and NON during the CPP test (Fig. 3a–b). NON::ChR2BF→lHb stimulation promoted CPP (Fig. 3c–e), mimicking responses observed in control AGG. Conversely, AGG::NpHR3BF→lHb stimulation induced CPA (Fig. 3f–h), mimicking responses observed in control NON. Neither NON::NpHR3BF→lHb or AGG::ChR2BF→lHb stimulation significantly affected the expression of CPP or CPA. Viral expression (Extended Data Figure 6a–f) and locomotor activity (Extended Data Figure 6g–j) was not different between conditions. These data confirm that BF-lHb circuitry modulates the rewarding component of aggressive behavior and is both necessary and sufficient for the expression of CPP in AGG and CPA in NON.

View Article: PubMed Central - PubMed

ABSTRACT

Maladaptive aggressive behavior is associated with a number of neuropsychiatric disorders1 and is thought to partly result from inappropriate activation of brain reward systems in response to aggressive or violent social stimuli2. Nuclei within the ventromedial hypothalamus3&ndash;5, extended amygdala6 and limbic7 circuits are known to encode initiation of aggression; however, little is known about the neural mechanisms that directly modulate the motivational component of aggressive behavior8. To address this, we established a mouse model to measure the valence of aggressive inter-male social interaction with a smaller subordinate intruder as reinforcement for the development of conditioned place preference (CPP). Aggressors (AGG) develop a CPP, while non-aggressors (NON) develop a conditioned place aversion (CPA), to the intruder-paired context. Further, we identify a functional GABAergic projection from the basal forebrain (BF) to the lateral habenula (lHb) that bi-directionally controls the valence of aggressive interactions. Circuit-specific silencing of GABAergic BF-lHb terminals of AGG with halorhodopsin (NpHR3.0) increases lHb neuronal firing and abolishes CPP to the intruder-paired context. Activation of GABAergic BF-lHb terminals of NON with channelrhodopsin (ChR2) decreases lHb neuronal firing and promotes CPP to the intruder-paired context. Lastly, we show that altering inhibitory transmission at BF-lHb terminals does not control the initiation of aggressive behavior. These results demonstrate that the BF-lHb circuit plays a critical role in regulating the valence of inter-male aggressive behavior and provide novel mechanistic insight into the neural circuits modulating aggression reward processing.

No MeSH data available.


Related in: MedlinePlus