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Chemogenetic modulation of histaminergic neurons in the tuberomamillary nucleus alters territorial aggression and wakefulness.

ABSTRACT: Designer receptor activated by designer drugs (DREADDs) techniques are widely used to modulate the activities of specific neuronal populations during behavioural tasks. However, DREADDs-induced modulation of histaminergic neurons in the tuberomamillary nucleus (HA^TMN neurons) has produced inconsistent effects on the sleep-wake cycle, possibly due to the use of Hdc-Cre mice driving Cre recombinase and DREADDs activity outside the targeted region. Moreover, previous DREADDs studies have not examined locomotor activity and aggressive behaviours, which are also regulated by brain histamine levels. In the present study, we investigated the effects of HA^TMN activation and inhibition on the locomotor activity, aggressive behaviours and sleep-wake cycle of Hdc-Cre mice with minimal non-target expression of Cre-recombinase. Chemoactivation of HA^TMN moderately enhanced locomotor activity in a novel open field. Activation of HA^TMN neurons significantly enhanced aggressive behaviour in the resident-intruder test. Wakefulness was increased and non-rapid eye movement (NREM) sleep decreased for an hour by HA^TMN chemoactivation. Conversely HA^TMN chemoinhibition decreased wakefulness and increased NREM sleep for 6 h. These changes in wakefulness induced by HA^TMN modulation were related to the maintenance of vigilance state. These results indicate the influences of HA^TMN neurons on exploratory activity, territorial aggression, and wake maintenance.

SUBMITTER: Naganuma F

PROVIDER: S-EPMC8429727 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:We recently developed a mouse model of appetitive operant aggression and reported that adult male outbred CD-1 mice lever-press for the opportunity to attack subordinate male mice and relapse to aggression seeking during abstinence. Here we studied the role of nucleus accumbens (NAc) dopamine receptor (Drd)1- and Drd2-expressing neurons in aggression self-administration and aggression seeking. We trained CD-1 mice to self-administer intruders (9 d, 12 trials/d) and tested them for aggression self-administration and aggression seeking on abstinence Day 1. We used immunohistochemistry and in situ hybridization to measure the neuronal activity marker Fos in the NAc, and cell-type-specific colocalization of Fos with Drd1- and Drd2-expressing neurons. To test the causal role of Drd1- and Drd2-expressing neurons, we validated a transgenic hybrid breeding strategy crossing inbred Drd1-Cre and Drd2-Cre transgenic mice with outbred CD-1 mice and used cell-type-specific Cre-DREADD (hM4Di) to inhibit NAc Drd1- and Drd2-expressing neuron activity. We found that aggression self-administration and aggression seeking induced higher Fos expression in NAc shell than in core, that Fos colocalized with Drd1 and Drd2 in both subregions, and that chemogenetic inhibition of Drd1-, but not Drd2-, expressing neurons decreased aggression self-administration and aggression seeking. Results indicate a cell-type-specific role of Drd1-expressing neurons that is critical for both aggression self-administration and aggression seeking. Our study also validates a simple breeding strategy between outbred CD-1 mice and inbred C57-based Cre lines that can be used to study cell-type and circuit mechanisms of aggression reward and relapse.SIGNIFICANCE STATEMENT Aggression is often comorbid with neuropsychiatric diseases, including drug addiction. One form, appetitive aggression, exhibits symptomatology that mimics that of drug addiction and is hypothesized to be due to dysregulation of addiction-related reward circuits. However, our mechanistic understanding of the circuitry modulating appetitive operant aggression is limited. Here we used a novel mouse model of aggression self-administration and relapse, in combination with immunohistochemistry, in situ hybridization, and chemogenetic manipulations to examine how cell types in the nucleus accumbens are recruited for, and control, operant aggression self-administration and aggression seeking on abstinence Day 1. We found that one population, dopamine receptor 1-expressing neurons, act as a critical modulator of operant aggression reward and aggression seeking.

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Chemogenetic modulation of histaminergic neurons in the tuberomamillary nucleus alters territorial aggression and wakefulness.

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