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The orbitofrontal cortex (OFC) supports flexible value representation and decision making and its dysfunction is implicated in affective disorders. In rodents and primates different OFC subdivisions fulfill different functions, like encoding rewarding/aversive stimuli. Although recent anatomical and functional investigations have been performed in mice, species differences in reward and value-encoding physiology call for deeper investigation of mouse OFC connectivity to better support translational research. Here, we compare density of retrograde inputs, axonal outputs and inter-subdivision connectivity, focusing on MO (medial-orbital), VO (ventral-orbital), (D)LO ((dorso)lateral-orbital) and AI (agranular insula). Central subdivisions (LO, VO) received dominant inputs from mediodorsal and submedius thalamic nuclei and projected respectively to medial prefrontal areas and sensory cortices. The striatal output was directed towards dorsal striatum, with reciprocal connection to/from brainstem dopaminergic areas. Input sources were more distributed for MO and AI, with reciprocal innervation to medial prefrontal cortices and amygdala, respectively. Striatal output was mainly to ventral striatum, and AI also received strong serotonergic innervation. Cluster analysis revealed that VO/LO, and to lesser extent MO/DLO, shared strong similar input distributions, distinct from AI. Output clustering separated VO targeting sensory areas and AI targeting amygdala. Intra-OFC connectivity suggested information flow preferentially from (D)LO (entry nodes), to VO, MO and finally AI (output node). We suggest a putative model integrating preferentially in-series, sensory-motor plans (at (D)LO), motivational state and cue-uncertainty (at VO/LO) and current goals (at MO), via AI modulating the amygdaloidal and ventral striatal outputs, thus proposing a prototype circuit to control emotional reactivity and decision-making in mouse OFC.

Satiation is essential for energy homeostasis and is dysregulated in metabolic disorders like obesity and eating disorders such as anorexia nervosa. While satiation engages a large neural network across brain regions, how the communication within this network depends on metabolic fluctuations is unclear. This study shows that nutrient access can affect neuron-to-neuron communication in this network by regulating excitatory synaptic plasticity through O-GlcNAc transferase (OGT) in αCaMKII satiation neurons in the paraventricular nucleus (PVN). Using cell-specific knockout mice and electrophysiological recordings, we demonstrate that OGT deletion in PVNαCaMKII neurons increases input resistance and neuronal excitability while preserving basic membrane electrical properties. Strikingly, feeding triggered a robust 3.8-fold increase in excitatory synaptic input in wild-type neurons, whereas OGT-knockout neurons failed to exhibit this feeding-induced synaptic activation and instead displayed a paradoxical trend towards decreased synaptic activity upon food intake. Furthermore, OGT deletion destabilized glucose-dependent synaptic responses, with knockout neurons displaying maladaptive depression of excitatory transmission in conditions where stability is normally preserved. These findings establish OGT as a nutrient-sensitive modulator of synaptic plasticity that ensures appropriate satiation signaling by coupling metabolic state to synaptic plasticity.

Little is known about estrous effects on brain microcircuits. We examined the accessory olfactory bulb (AOB) in vivo, in anesthetized naturally cycling females, as model microcircuit receiving coital somatosensory information. Whole-cell recordings demonstrate that output neurons are relatively hyperpolarized in estrus and unexpectedly fire high frequency bursts of action potentials. To mimic coitus, a calibrated artificial vagino-cervical stimulation (aVCS) protocol was devised. aVCS evoked stimulus-locked local field responses in the interneuron layer independent of estrous stage. The response is sensitive to α1-adrenergic receptor blockade, as expected since aVCS increases norepinephrine release in AOB. Intriguingly, only in estrus does aVCS inhibit AOB spike output. Estrus-specific output reduction coincides with prolonged aVCS activation of inhibitory interneurons. Accordingly, in estrus the AOB microcircuit sets the stage for coital stimulation to inhibit the output neurons, possibly via high frequency bursting-dependent enhancement of reciprocal synapse efficacy between inter- and output neurons.

Background: Auditory hallucinations (which occur when the distinction between thoughts and perceptions is blurred) are common in psychotic disorders. The orbitofrontal cortex (OFC) may be implicated, because it receives multiple inputs, including sound and affective value via the amygdala, orchestrating complex emotional responses. We aimed to elucidate the circuit and neuromodulatory mechanisms that underlie the processing of emotionally salient auditory stimuli in the OFC — mechanisms that may be involved in auditory hallucinations. Methods: We identified the cortico-cortical connectivity conveying auditory information to the mouse OFC; its sensitivity to neuromodulators involved in psychosis and postpartum depression, such as dopamine and neurosteroids; and its sensitivity to sensory gating (defective in dysexecutive syndromes). Results: Retrograde tracers in OFC revealed input cells in all auditory cortices. Acoustic responses were abolished by pharmacological and chemogenetic inactivation of the above-identified pathway. Acoustic responses in the OFC were reduced by local dopaminergic agonists and neurosteroids. Noticeably, apomorphine action lasted longer in the OFC than in auditory areas, and its effect was modality-specific (augmentation for visual responses), whereas neurosteroid action was sex-specific. Finally, acoustic responses in the OFC reverberated to the auditory association cortex via feedback connections and displayed sensory gating, a phenomenon of local origin, given that it was not detectable in input auditory cortices. Limitations: Although our findings were for mice, connectivity and sensitivity to neuromodulation are conserved across mammals. Conclusion: The corticocortical loop from the auditory association cortex to the OFC is dramatically sensitive to dopamine and neurosteroids. This suggests a clinically testable circuit behind auditory hallucinations. The function of OFC input–output circuits can be studied in mice with targeted and clinically relevant mutations related to their response to emotionally salient sounds.

Genetic microdeletion at the 22q11 locus is associated with very high risk for schizophrenia. The 22q11.2 microdeletion (Df(h22q11)/+) mouse model shows cognitive deficits observed in this disorder, some of which can be linked to dysfunction of the prefrontal cortex (PFC). We used behavioral (n = 10 per genotype), electrophysiological (n = 7 per genotype per group), and neuroanatomical (n = 5 per genotype) techniques to investigate schizophrenia-related pathology of Df(h22q11)/+ mice, which showed a significant decrease in the total number of parvalbumin positive interneurons in the medial PFC. The Df(h22q11)/+ mice when tested on PFC-dependent behavioral tasks, including gambling tasks, perform significantly worse than control animals while exhibiting normal behavior on hippocampus-dependent tasks. They also show a significant decrease in hippocampus-medial Prefrontal cortex (H-PFC) synaptic plasticity (long-term potentiation, LTP). Acute platform stress almost abolished H-PFC LTP in both wild-type and Df(h22q11)/+ mice. H-PFC LTP was restored to prestress levels by clozapine (3 mg/kg i.p.) in stressed Df(h22q11)/+ mice, but the restoration of stress-induced LTP, while significant, was similar between wild-type and Df(h22q11)/+ mice. A medial PFC dysfunction may underlie the negative and cognitive symptoms in human 22q11 deletion carriers, and these results are relevant to the current debate on the utility of clozapine in such subjects.

We previously analyzed the arborization patterns of rat ventral pallidal (VP) axons that coursed caudally to innervate the thalamus and brainstem (Tripathi et al. in Brain Struct Funct 218:1133-1157, 2013). Here, we have reconstructed 16 previously undetected axons from the same tracer deposits that follow a more lateral trajectory. Virtually all 16 axons emanating from the different VP compartments collateralized in the extended amygdala system (EAS) and amygdaloid complex. The most frequent targets of axons from the lateral and medial (VPm) VP compartments were the rostral sublenticular extended amygdala, the extended amygdala (EA), the central nucleus of the amygdala and the posterior part of the basolateral amygdaloid nucleus. In contrast, axons from the rostral extension of the VP preferentially innervated the anterior amygdaloid area, the magnocellular preoptic nucleus, and the anterior part of the basomedial amygdaloid nucleus. We additionally found and reconstructed a single corticopetal axon arising from the VPm. The new results show that both direct and indirect projections from the basolateral complex and EAS to the ventral striatopallidal system are reciprocated by VP projections, and suggest that the systems can be activated simultaneously. The results additionally suggest that the amygdaloid complex and cortex are innervated separately from the VP. Finally, the combination of new and previous data indicate that approximately 84 % of VP axons (88/105) participate in basal ganglia circuits, 15 % (16/105) target the amygdaloid complex, and less than 1 % innervate the cortex.

This is the first study of the electrophysiological response of accessory olfactory bulb (AOB) output neurons to vagino-cervical stimulation by in vivo whole-cell recordings, allowing for measurements at synaptic input and spike output level in identified microcircuit cell types in naturally cycling mice. AOB is relaying specialized odorous information and e.g. shows plasticity essential for formation of a vomeronasal organ (VNO)-pheromonal memory of the mating male. Thus, not only VNO-pheromonal information, but also representation of coital somatosensory information needs to reach AOB. AOB in vivo responses to VNO-pheromones does not correlate in time to stimulus. We find that vagino-cervical stimuli evoke a stimulus-locked response in AOB regardless if the female is in estrus or not, and the response is sensitive to noradrenergic α1-adrenergic receptor blockade. By retrograde labeling we confirm that norepinephrine-producing locus coeruleus neurons innervate the AOB and functional anatomy demonstrated that vagino-cervical information reaches locus coeruleus in both estrus and diestrus. The spontaneous activity of mitral-tufted output neurons show propensity to fire bursts of spikes specifically during estrus suggesting state-dependent excitability of the network. Intriguingly, only during estrus do the output neurons show norepinephrine-dependent, dendro-dendritic inhibition of spike output during vagino-cervical stimulation, which is accompanied by longer activation of inhibitory granule cell layer of AOB. Thus, the estrous state of the circuit appears required for coital stimulation to evoke synaptic inhibition in main output neurons of the microcircuit, which may contribute to formation of memory of the mating male, possibly via burst-dependent increase of dendro-dendritic inhibition