Motivational valence is determined by striatal melanocortin 4 receptors

It is critical for survival to assign positive or negative valence to salient stimuli in a correct manner. Accordingly, harmful stimuli and internal states characterized by perturbed homeostasis are accompanied by discomfort, unease, and aversion. Aversive signaling causes extensive suffering during chronic diseases, including inflammatory conditions, cancer, and depression. Here, we investigated the role of melanocortin 4 receptors (MC4Rs) in aversive processing using genetically modified mice and a behavioral test in which mice avoid an environment that they have learned to associate with aversive stimuli. In normal mice, robust aversions were induced by systemic inflammation, nausea, pain, and κ opioid receptor- induced dysphoria. In sharp contrast, mice lacking MC4Rs displayed preference or indifference toward the aversive stimuli. The unusual flip from aversion to reward in mice lacking MC4Rs was dopamine dependent and associated with a change from decreased to increased activity of the dopamine system. The responses to aversive stimuli were normalized when MC4Rs were reexpressed on dopamine D1 receptor-expressing cells or in the striatum of mice otherwise lacking MC4Rs. Furthermore, activation of arcuate nucleus proopiomelanocortin neurons projecting to the ventral striatum increased the activity of striatal neurons in an MC4R-dependent manner and elicited aversion. Our findings demonstrate that melanocortin signaling through striatal MC4Rs is critical for assigning negative motivational valence to harmful stimuli

Inactivation of the basolateral amygdala impairs the retrieval of recent and remote taste-potentiated odor aversion memory

International audienceMemory reorganization as a time-dependent process can be investigated using various learning tasks such as the taste-potentiated odor aversion (TPOA). In this paradigm rats acquire a strong aversion to an olfactory cue presented simultaneously with a gustatory cue. Together these cues are paired with a delayed visceral illness. The basolateral amygdaloid nucleus (BLA) plays a key role in TPOA acquisition but its involvement in retrieval remains unclear. We investigated the involvement of the BLA in either recent or remote retrieval of TPOA. In each case, the number of licks observed in response to the presentation of either the odor or the taste was used to assess retrieval. Before the retrieval test, rats received a bilateral infusion of lidocaine to inactivate the BLA. We observed that both recent and remote TPOA retrieval tests induced by the odor presentation were disrupted in the lidocaine-injected rats. By contrast, the BLA inactivation had no effect upon the aversion towards the taste cue regardless of the time of retrieval. The present study provides evidence that BLA functioning is necessary for retrieval of aversive odor memory, even with a long post-acquisition delay

Suppression of c-fos expression in the amygdala impairs the retrieval of taste potentiated odor aversion

Suppression of c-fos expression in the amygdala impairs the retrieval of taste potentiated odor aversion. 18. Congress of european chemoreception research organization, ECR

Prostaglandin production selectively in brain endothelial cells is both necessary and sufficient for eliciting fever

Fever is known to be elicited by prostaglandin E2 acting on the brain, but its origin has remained disputed. We show in mice that selective deletion of prostaglandin synthesis in brain endothelial cells, but not in neural cells or myeloid cells, abolished fever induced by intravenous administration of lipopolysaccharide and that selective rescue of prostaglandin synthesis in brain endothelial cells reinstated fever. These data demonstrate that prostaglandin production in brain endothelial cells is both necessary and sufficient for eliciting fever.

Ontogeny of odor-LiCl vs. odor-shock learning : Similar behaviors but divergent ages of functional amygdala emergence

Both odor-preference and odor-aversion learning occur in perinatal pups before the maturation of brain structures that support this learning in adults. To characterize the development of odor learning, we compared three learning paradigms: (1) odor-LiCl (0.3M; 1% body weight, ip) and (2) odor-1.2-mA shock (hindlimb, 1sec)ￜboth of which consistently produce odor-aversion learning throughout life and (3) odor-0.5-mA shock, which produces an odor preference in early life but an odor avoidance as pups mature. Pups were trained at postnatal day (PN) 7ￜ8, 12ￜ13, or 23ￜ24, using odor-LiCl and two odor-shock conditioning paradigms of odor-0.5-mA shock and odor-1.2-mA shock. Here we show that in the youngest pups (PN7ￜ8), odor-preference learning was associated with activity in the anterior piriform (olfactory) cortex, while odor-aversion learning was associated with activity in the posterior piriform cortex. At PN12ￜ13, when all conditioning paradigms produced an odor aversion, the odor-0.5-mA shock, odor-1.2-mA shock, and odor-LiCl all continued producing learning-associated changes in the posterior piriform cortex. However, only odor-0.5-mA shock induced learning-associated changes within the basolateral amygdala. At weaning (PN23ￜ24), all learning paradigms produced learning-associated changes in the posterior piriform cortex and basolateral amygdala complex. These results suggest at least two basic principles of the development of the neurobiology of learning: (1) Learning that appears similar throughout development can be supported by neural systems showing very robust developmental changes, and (2) the emergence of amygdala function depends on the learning protocol and reinforcement condition being assessed

Fever During Localized Inflammation in Mice Is Elicited by a Humoral Pathway and Depends on Brain Endothelial Interleukin-1 and Interleukin-6 Signaling and Central EP3 Receptors

We examined the signaling route for fever during localized inflammation in male and female mice, elicited by casein injection into a preformed air pouch. The localized inflammation gave rise to high concentrations of prostaglandins of the E species (PGE(2)) and cytokines in the air pouch and elevated levels of these inflammatory mediators in plasma. There were also elevated levels of PGE(2) in the cerebrospinal fluid, although there was little evidence for PGE(2) synthesis in the brain. Global deletion of the PGE(2) prostaglandin E receptor 3 (EP3) abolished the febrile response as did deletion of the EP3 receptor in neural cells, whereas its deletion on peripheral nerves had no effect, implying that PGE(2) action on this receptor in the CNS elicited the fever. Global deletion of the interleukin-1 receptor type 1 (IL-1R1) also abolished the febrile response, whereas its deletion on neural cells or peripheral nerves had no effect. However, deletion of the IL-1R1 on brain endothelial cells, as well as deletion of the interleukin-6 receptor a on these cells, attenuated the febrile response. In contrast, deletion of the PGE(2) synthesizing enzymes cyclooxygenase-2 and microsomal prostaglandin synthase-1 in brain endothelial cells, known to attenuate fever evoked by systemic inflammation, had no effect. We conclude that fever during localized inflammation is not mediated by neural signaling from the inflamed site, as previously suggested, but is dependent on humoral signaling that involves interleukin actions on brain endothelial cells, probably facilitating PGE(2) entry into the brain from the circulation and hence representing a mechanism distinct from that at work during systemic inflammation.Funding Agencies|Swedish Research CouncilSwedish Research CouncilEuropean Commission [2020-00881, 201802929]; Swedish Brain Foundation [FO20190033]; Swedish Cancer Foundation [190304]; Knut and Alice Wallenberg FoundationKnut &amp; Alice Wallenberg Foundation [WAF 2012]</p

The generation of immune-induced fever and emotional stress-induced hyperthermia in mice does not involve brown adipose tissue thermogenesis

We examined the role of brown adipose tissue (BAT) for fever and emotional stress-induced hyperthermia. Wild-type and uncoupling protein-1 (UCP-1) knockout mice were injected with lipopolysaccharide intraperitoneally or intravenously, or subjected to cage exchange, and body temperature monitored by telemetry. Both genotypes showed similar febrile responses to immune challenge and both displayed hyperthermia to emotional stress. Neither procedure resulted in the activation of BAT, such as the induction of UCP-1 or peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) mRNA, or reduced BAT weight and triglyceride content. In contrast, in mice injected with a beta (3) agonist, UCP-1 and PGC-1 alpha were strongly induced, and BAT weight and triglyceride content reduced. Both lipopolysaccharide and the beta (3) agonist, and emotional stress, induced UCP-3 mRNA in skeletal muscle. A beta (3) antagonist did not attenuate lipopolysaccharide-induced fever, but augmented body temperature decrease and inhibited BAT activation when mice were exposed to cold. An alpha (1)/alpha (2b) antagonist or a 5HT(1A) agonist, which inhibit vasoconstriction, abolished lipopolysaccharide-induced fever, but had no effect on emotional stress-induced hyperthermia. These findings demonstrate that in mice, UCP-1-mediated BAT thermogenesis does not take part in inflammation-induced fever, which is dependent on peripheral vasoconstriction, nor in stress-induced hyperthermia. However, both phenomena may involve UCP-3-mediated muscle thermogenesis.Funding Agencies|Swedish Research CouncilSwedish Research Council [2016-01301]; Vetenskapsradet (VR) [2016-01301]; Brain Foundation [FO2019-0033]; Hjarnfonden (Swedish Brain Foundation) [FO2019-0033]</p

Early-life stress disrupts attachment learning: the role of amygdala corticosterone, locus coeruleus, corticotropin releasing hormone, and olfactory bulb norepinephrine

Infant rats require maternal odor learning to guide pups&apos; proximity-seeking of the mother and nursing. Maternal odor learning occurs using a simple learning circuit including robust olfactory bulb norepinephrine (NE), release from the locus ceruleus (LC), and amygdala suppression by low corticosterone (CORT). Early-life stress increases NE but also CORT, and we questioned whether early-life stress disrupted attachment learning and its neural correlates [2-deoxyglucose (2-DG) autoradiography]. Neonatal rats were normally reared or stressed-reared during the first 6 d of life by providing the mother with insufficient bedding for nest building and were odor-0.5 mA shock conditioned at 7 d old. Normally reared paired pups exhibited typical odor approach learning and associated olfactory bulb enhanced 2-DG uptake. However, stressed-reared pups showed odor avoidance learning and both olfactory bulb and amygdala 2-DG uptake enhancement. Furthermore, stressed-reared pups had elevated CORT levels, and systemic CORT antagonist injection reestablished the age-appropriate odor-preference learning, enhanced olfactory bulb, and attenuated amygdala 2-DG. We also assessed the neural mechanism for stressed-reared pups&apos; abnormal behavior in a more controlled environment by injecting normally reared pups with CORT. This was sufficient to produce odor aversion, as well as dual amygdala and olfactory bulb enhanced 2-DG uptake. Moreover, we assessed a unique cascade of neural events for the aberrant effects of stress rearing: the amygdala-LC-olfactory bulb pathway. Intra-amygdala CORT or intra-LC corticotropin releasing hormone (CRH) infusion supported aversion learning with intra-LC CRH infusion associated with increased olfactory bulb NE (microdialysis). These results suggest that early-life stress disturbs attachment behavior via a unique cascade of events (amygdala-LC-olfactory bulb)

Melanocortin-4 receptors on neurons in the parabrachial nucleus mediate inflammation-induced suppression of food-seeking behavior

Anorexia is a common symptom during infectious and inflammatory disease. Here we examined the role ofmelanocortin-4 receptors (MC4Rs) in inflammation-induced anorexia. Mice with transcriptional blockage of theMC4Rs displayed the same reduction of food intake following peripheral injection of lipopolysaccharide as wildtype mice but were protected against the anorexic effect of the immune challenge in a test in which fastedanimals were to use olfactory cues to find a hidden cookie. By using selective virus-mediated receptor reexpression we demonstrate that the suppression of the food-seeking behavior is subserved by MC4Rs in thebrain stem parabrachial nucleus, a central hub for interoceptive information involved in the regulation of foodintake. Furthermore, the selective expression of MC4R in the parabrachial nucleus also attenuated the bodyweight increase that characterizes MC4R KO mice. These data extend on the functions of the MC4Rs and showthat MC4Rs in the parabrachial nucleus are critically involved in the anorexic response to peripheral inflammation but also contribute to body weight homeostasis during normal conditions. Funding agencies: the Swedish Cancer Foundation (22 2338 Pj); Swedish Research Council (2020-00881, 2022-00952), Swedish Brain Foundation (FO2021-0010, FO2022-0114) and Knut och Alice Wallenbergs Stiftelse (WAF 2012).</p

Auditory Stimulation Dishabituates Olfactory Responses via Noradrenergic Cortical Modulation

Dishabituation is a return of a habituated response if context or contingency changes. In the mammalian olfactory system, metabotropic glutamate receptor mediated synaptic depression of cortical afferents underlies short-term habituation to odors. It was hypothesized that a known antagonistic interaction between these receptors and norepinephrine -receptors provides a mechanism for dishabituation. The results demonstrate that a 108 dB siren induces a two-fold increase in norepinephrine content in the piriform cortex. The same auditory stimulus induces dishabituation of odor-evoked heart rate orienting bradycardia responses in awake rats. Finally, blockade of piriform cortical norepinephrine -receptors with bilateral intracortical infusions of propranolol (100  M) disrupts auditory-induced dishabituation of odor-evoked bradycardia responses. These results provide a cortical mechanism for a return of habituated sensory responses following a cross-modal alerting stimulus