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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 circuit tracing and GABAergic cell-type specificity(a) Schematic of viral tracing strategy. Representative BF viral infection with (b) AAV2-hSyn-eYFP, scale bar 500 μm. Histological analysis of viral infection with (c) AAV2-hSyn-eYFP (F3,11 = 223.0, one-way ANOVA ***P < 0.0001, post hoc test, ***P < 0.0001; n = 3 mice, 3 slices/mouse) across adjacent anatomical regions. (d) Whole-cell electrophysiological recordings and (e) representative traces of lHb neurons photostimulated with AAV2-hSyn-ChR2.0 in the absence or presence of bath applied GABAA receptor antagonist gabazine (4 μm; F2,7 = 220, one-way ANOVA P < 0.05; post hoc test, ***P < 0.001, n =4,2,2 cells from 2 mice). (f) Optically evoked IPSC response delay (n= 21 oIPSC events, 2 mice). (g) Representative images of eYFPBF→lHb terminal co-localization between vesicular GABA transporter (top), and not vesicular glutamate transporter 1 (bottom). Scale bar is 10 μm in all panels; white arrows indicate colocalization within insets. VGAT, vesicular GABA transporter; VGLUT, vesicular glutamate transporter 1; DAPI, 4′,6-diamidino-2-phenylindole; BF, basal forebrain; lHb, lateral habenula; pLS, posterior lateral septum; MS, medial septum. Summary data are represented as mean ± s.e.m.
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Figure 8: BF-lHb circuit tracing and GABAergic cell-type specificity(a) Schematic of viral tracing strategy. Representative BF viral infection with (b) AAV2-hSyn-eYFP, scale bar 500 μm. Histological analysis of viral infection with (c) AAV2-hSyn-eYFP (F3,11 = 223.0, one-way ANOVA ***P < 0.0001, post hoc test, ***P < 0.0001; n = 3 mice, 3 slices/mouse) across adjacent anatomical regions. (d) Whole-cell electrophysiological recordings and (e) representative traces of lHb neurons photostimulated with AAV2-hSyn-ChR2.0 in the absence or presence of bath applied GABAA receptor antagonist gabazine (4 μm; F2,7 = 220, one-way ANOVA P < 0.05; post hoc test, ***P < 0.001, n =4,2,2 cells from 2 mice). (f) Optically evoked IPSC response delay (n= 21 oIPSC events, 2 mice). (g) Representative images of eYFPBF→lHb terminal co-localization between vesicular GABA transporter (top), and not vesicular glutamate transporter 1 (bottom). Scale bar is 10 μm in all panels; white arrows indicate colocalization within insets. VGAT, vesicular GABA transporter; VGLUT, vesicular glutamate transporter 1; DAPI, 4′,6-diamidino-2-phenylindole; BF, basal forebrain; lHb, lateral habenula; pLS, posterior lateral septum; MS, medial septum. Summary data are represented as mean ± s.e.m.

Mentions: Clinical2,12 and pre-clinical8 studies have implicated basal forebrain (BF) structures, such as the nucleus accumbens (NAc), lateral septum (LS), and diagonal band nuclei (DBN), as potentially important brain regions controlling aggression-related behaviors. However, there has been limited functional evidence that the BF, or its projections, directly modulate the rewarding aspects of aggression. To define BF projections, we injected an adeno-associated virus (AAV) vector expressing enhanced yellow fluorescent protein (eYFP) under a neuronal-specific human synapsin (hSyn) promoter (AAV2-hSyn-eYFP) into the BF of CD-1 mice (Fig. 2a–c, top; Extended Data Figure 4a–c) targeted specifically to the more anterior septo-accumbal transition zone of the basal forebrain13 and observe a prominent axonal projection to the lHb (Fig. 2b, top).


Basal forebrain projections to the lateral habenula modulate aggression reward
BF-lHb circuit tracing and GABAergic cell-type specificity(a) Schematic of viral tracing strategy. Representative BF viral infection with (b) AAV2-hSyn-eYFP, scale bar 500 μm. Histological analysis of viral infection with (c) AAV2-hSyn-eYFP (F3,11 = 223.0, one-way ANOVA ***P < 0.0001, post hoc test, ***P < 0.0001; n = 3 mice, 3 slices/mouse) across adjacent anatomical regions. (d) Whole-cell electrophysiological recordings and (e) representative traces of lHb neurons photostimulated with AAV2-hSyn-ChR2.0 in the absence or presence of bath applied GABAA receptor antagonist gabazine (4 μm; F2,7 = 220, one-way ANOVA P < 0.05; post hoc test, ***P < 0.001, n =4,2,2 cells from 2 mice). (f) Optically evoked IPSC response delay (n= 21 oIPSC events, 2 mice). (g) Representative images of eYFPBF→lHb terminal co-localization between vesicular GABA transporter (top), and not vesicular glutamate transporter 1 (bottom). Scale bar is 10 μm in all panels; white arrows indicate colocalization within insets. VGAT, vesicular GABA transporter; VGLUT, vesicular glutamate transporter 1; DAPI, 4′,6-diamidino-2-phenylindole; BF, basal forebrain; lHb, lateral habenula; pLS, posterior lateral septum; MS, medial septum. Summary data are represented as mean ± s.e.m.
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Figure 8: BF-lHb circuit tracing and GABAergic cell-type specificity(a) Schematic of viral tracing strategy. Representative BF viral infection with (b) AAV2-hSyn-eYFP, scale bar 500 μm. Histological analysis of viral infection with (c) AAV2-hSyn-eYFP (F3,11 = 223.0, one-way ANOVA ***P < 0.0001, post hoc test, ***P < 0.0001; n = 3 mice, 3 slices/mouse) across adjacent anatomical regions. (d) Whole-cell electrophysiological recordings and (e) representative traces of lHb neurons photostimulated with AAV2-hSyn-ChR2.0 in the absence or presence of bath applied GABAA receptor antagonist gabazine (4 μm; F2,7 = 220, one-way ANOVA P < 0.05; post hoc test, ***P < 0.001, n =4,2,2 cells from 2 mice). (f) Optically evoked IPSC response delay (n= 21 oIPSC events, 2 mice). (g) Representative images of eYFPBF→lHb terminal co-localization between vesicular GABA transporter (top), and not vesicular glutamate transporter 1 (bottom). Scale bar is 10 μm in all panels; white arrows indicate colocalization within insets. VGAT, vesicular GABA transporter; VGLUT, vesicular glutamate transporter 1; DAPI, 4′,6-diamidino-2-phenylindole; BF, basal forebrain; lHb, lateral habenula; pLS, posterior lateral septum; MS, medial septum. Summary data are represented as mean ± s.e.m.
Mentions: Clinical2,12 and pre-clinical8 studies have implicated basal forebrain (BF) structures, such as the nucleus accumbens (NAc), lateral septum (LS), and diagonal band nuclei (DBN), as potentially important brain regions controlling aggression-related behaviors. However, there has been limited functional evidence that the BF, or its projections, directly modulate the rewarding aspects of aggression. To define BF projections, we injected an adeno-associated virus (AAV) vector expressing enhanced yellow fluorescent protein (eYFP) under a neuronal-specific human synapsin (hSyn) promoter (AAV2-hSyn-eYFP) into the BF of CD-1 mice (Fig. 2a–c, top; Extended Data Figure 4a–c) targeted specifically to the more anterior septo-accumbal transition zone of the basal forebrain13 and observe a prominent axonal projection to the lHb (Fig. 2b, top).

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