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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 does not initiate attack but modulates aggression severity(a) Schematic of optogenetic (a) viral infection strategy and (b) aggression procedure. NON (c) attack latency, (d) attack duration, (e) social exploration and (f) non-social exploration behaviors in pretest and test sessions (non-significant, n = 7–8/group). AGG (g) attack latency (F2,42 = 6.01, two-way ANOVA P <0.001, *P<0.05, n = 7–9/group), (h) attack duration (F2,42 = 5.666, two-way ANOVA P <0.001, *P<0.05, n = 7–9/group), (i) social exploration and (j) non-social exploration behaviors in pretest and test sessions. NON, non-aggressor; AGG, aggressor; lHb, lateral habenula; BF, basal forebrain.
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Figure 4: BF-lHb does not initiate attack but modulates aggression severity(a) Schematic of optogenetic (a) viral infection strategy and (b) aggression procedure. NON (c) attack latency, (d) attack duration, (e) social exploration and (f) non-social exploration behaviors in pretest and test sessions (non-significant, n = 7–8/group). AGG (g) attack latency (F2,42 = 6.01, two-way ANOVA P <0.001, *P<0.05, n = 7–9/group), (h) attack duration (F2,42 = 5.666, two-way ANOVA P <0.001, *P<0.05, n = 7–9/group), (i) social exploration and (j) non-social exploration behaviors in pretest and test sessions. NON, non-aggressor; AGG, aggressor; lHb, lateral habenula; BF, basal forebrain.

Mentions: To determine if BF-lHb neuronal activity regulates the initiation or intensity of aggressive behavior, we utilized ChR2BF→lHb and NpHR3BF→lHb (Fig. 4a) in AGG and NON during home cage resident-intruder testing (Fig. 4b). Neither activation nor inhibition of BF-lHb terminals resulted in initiation of aggressive behavior (Fig. 4c–d), nor did it modulate social (Fig. 4e) and non-social (Fig. 4f) exploratory behaviors in NON mice. Similarly, AGG::ChR2BF→lHb stimulation failed to initiate immediate attack behavior, as indexed by no change in attack latency (Fig. 4g). However, AGG::ChR2BF→lHb and AGG::NpHR3BF→lHb stimulation bi-directionally modulated the severity of the aggressive behavior relative to each other, though a nonsignificant trend was observed when either were compared to AGG::GFPBF→lHb (Fig. 4h). As observed in NON, AGG::ChR2BF→lHb and AGG::NpHR3BF→lHb photostimulation failed to alter either social (Fig. 4i) or non-social (Fig. 4j) exploratory behaviors. These data indicate that the BF-lHb circuit is important in modulating the intensity of aggressive behavior; however, it is not a traditional attack initiation area.


Basal forebrain projections to the lateral habenula modulate aggression reward
BF-lHb does not initiate attack but modulates aggression severity(a) Schematic of optogenetic (a) viral infection strategy and (b) aggression procedure. NON (c) attack latency, (d) attack duration, (e) social exploration and (f) non-social exploration behaviors in pretest and test sessions (non-significant, n = 7–8/group). AGG (g) attack latency (F2,42 = 6.01, two-way ANOVA P <0.001, *P<0.05, n = 7–9/group), (h) attack duration (F2,42 = 5.666, two-way ANOVA P <0.001, *P<0.05, n = 7–9/group), (i) social exploration and (j) non-social exploration behaviors in pretest and test sessions. NON, non-aggressor; AGG, aggressor; lHb, lateral habenula; BF, basal forebrain.
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Figure 4: BF-lHb does not initiate attack but modulates aggression severity(a) Schematic of optogenetic (a) viral infection strategy and (b) aggression procedure. NON (c) attack latency, (d) attack duration, (e) social exploration and (f) non-social exploration behaviors in pretest and test sessions (non-significant, n = 7–8/group). AGG (g) attack latency (F2,42 = 6.01, two-way ANOVA P <0.001, *P<0.05, n = 7–9/group), (h) attack duration (F2,42 = 5.666, two-way ANOVA P <0.001, *P<0.05, n = 7–9/group), (i) social exploration and (j) non-social exploration behaviors in pretest and test sessions. NON, non-aggressor; AGG, aggressor; lHb, lateral habenula; BF, basal forebrain.
Mentions: To determine if BF-lHb neuronal activity regulates the initiation or intensity of aggressive behavior, we utilized ChR2BF→lHb and NpHR3BF→lHb (Fig. 4a) in AGG and NON during home cage resident-intruder testing (Fig. 4b). Neither activation nor inhibition of BF-lHb terminals resulted in initiation of aggressive behavior (Fig. 4c–d), nor did it modulate social (Fig. 4e) and non-social (Fig. 4f) exploratory behaviors in NON mice. Similarly, AGG::ChR2BF→lHb stimulation failed to initiate immediate attack behavior, as indexed by no change in attack latency (Fig. 4g). However, AGG::ChR2BF→lHb and AGG::NpHR3BF→lHb stimulation bi-directionally modulated the severity of the aggressive behavior relative to each other, though a nonsignificant trend was observed when either were compared to AGG::GFPBF→lHb (Fig. 4h). As observed in NON, AGG::ChR2BF→lHb and AGG::NpHR3BF→lHb photostimulation failed to alter either social (Fig. 4i) or non-social (Fig. 4j) exploratory behaviors. These data indicate that the BF-lHb circuit is important in modulating the intensity of aggressive behavior; however, it is not a traditional attack initiation area.

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