Activation of CGRP neurons in the parabrachial nucleus suppresses addictive behavior.

Punishment such as electric shock or physical discipline employs a mixture of physical pain and emotional distress to induce behavior modification. However, a neural circuit that produces behavior modification by selectively focusing the emotional component, while bypassing the pain typically induced by peripheral nociceptor activation, is not well studied. Here, we show that genetically silencing the activity of neurons expressing calcitonin gene-related peptide (CGRP) in the parabrachial nucleus blocks the suppression of addictive-like behavior induced by footshock. Furthermore, activating CGRP neurons suppresses not only addictive behavior induced by self-stimulating dopamine neurons but also behavior resulting from self-administering cocaine, without eliciting nocifensive reactions. Moreover, among multiple downstream targets of CGRP neurons, terminal activation of CGRP in the central amygdala is effective, mimicking the results of cell body stimulation. Our results indicate that unlike conventional electric footshock, stimulation of CGRP neurons does not activate peripheral nociceptors but effectively curb addictive behavior.

SELENBP1 overexpression in the prefrontal cortex underlies negative symptoms of schizophrenia.

The selenium-binding protein 1 (SELENBP1) has been reported to be up-regulated in the prefrontal cortex (PFC) of schizophrenia patients in postmortem reports. However, no causative link between SELENBP1 and schizophrenia has yet been established. Here, we provide evidence linking the upregulation of SELENBP1 in the PFC of mice with the negative symptoms of schizophrenia. We verified the levels of SELENBP1 transcripts in postmortem PFC brain tissues from patients with schizophrenia and matched healthy controls. We also generated transgenic mice expressing human SELENBP1 (hSELENBP1 Tg) and examined their neuropathological features, intrinsic firing properties of PFC 2/3-layer pyramidal neurons, and frontal cortex (FC) electroencephalographic (EEG) responses to auditory stimuli. Schizophrenia-like behaviors in hSELENBP1 Tg mice and mice expressing Selenbp1 in the FC were assessed. SELENBP1 transcript levels were higher in the brains of patients with schizophrenia than in those of matched healthy controls. The hSELENBP1 Tg mice displayed negative endophenotype behaviors, including heterotopias- and ectopias-like anatomical deformities in upper-layer cortical neurons and social withdrawal, deficits in nesting, and anhedonia-like behavior. Additionally, hSELENBP1 Tg mice exhibited reduced excitabilities of PFC 2/3-layer pyramidal neurons and abnormalities in EEG biomarkers observed in schizophrenia. Furthermore, mice overexpressing Selenbp1 in FC showed deficits in sociability. These results suggest that upregulation of SELENBP1 in the PFC causes asociality, a negative symptom of schizophrenia.

A dopamine-dependent mechanism for Reward-induced modification of Fear memories.

A positive mental state has been shown to modulate fear-related emotions associated with the recall of fear memories. These, and other observations suggest the presence of central brain mechanisms for affective states to interact. The neurotransmitter dopamine is important for both Reward- and fear-related processes, but it is unclear whether dopamine contributes to such affective interactions. Here, we show that precisely timed Reward-induced activation of dopamine neurons in mice potently modifies fear memories and enhances their extinction. This Reward-based switch in fear states is associated with changes in dopamine release and dopamine-dependent regulation of fear encoding in the central amygdala (CeA). These data provide a central mechanism for Reward-induced modification of fear states that have broad implications for treating generalized fear disorders.

Conditioned flight response in female rats to naturalistic threat is estrous-cycle dependent.

Despite the prevalent expression of freezing behavior following Pavlovian fear conditioning, a growing body of literature suggests potential sex differences in defensive responses. Our study investigated how female defensive behaviors are expressed in different threat situations and modulated by the estrous cycle. We aimed to compare freezing and flight-like responses during the acquisition and retrieval of fear conditioning using two distinct unconditioned stimuli (US) in two different spatial configurations: (1) electrical footshock (FUS) in a small, conventional enclosure with a grid floor, and (2) a predator-like robot (PUS) in a spacious, open arena. Fear conditioning with FUS showed no substantial differences between male and female rats of two different estrous cycles (proestrus and diestrus) in the levels of freezing and flight. However, when PUS was employed, proestrus female rats showed significantly more flight responses to the CS during both acquisition and the retrieval compared to the male and diestrus female rats. Taken together, our findings suggest that hormonal influences on the choice of defensive strategies in threat situations are significantly modulated by both the type of US and the spatial configuration of the environment.

Neural mechanism of acute stress regulation by trace aminergic signalling in the lateral habenula in male mice.

Stress management is necessary for vertebrate survival. Chronic stress drives depression by excitation of the lateral habenula (LHb), which silences dopaminergic neurons in the ventral tegmental area (VTA) via GABAergic neuronal projection from the rostromedial tegmental nucleus (RMTg). However, the effect of acute stress on this LHb-RMTg-VTA pathway is not clearly understood. Here, we used fluorescent in situ hybridisation and in vivo electrophysiology in mice to show that LHb aromatic L-amino acid decarboxylase-expressing neurons (D-neurons) are activated by acute stressors and suppress RMTg GABAergic neurons via trace aminergic signalling, thus activating VTA dopaminergic neurons. We show that the LHb regulates RMTg GABAergic neurons biphasically under acute stress. This study, carried out on male mice, has elucidated a molecular mechanism in the efferent LHb-RMTg-VTA pathway whereby trace aminergic signalling enables the brain to manage acute stress by preventing the hypoactivity of VTA dopaminergic neurons.