Abstract:
Responses of the insular cortex (IC) and amygdala to stimuli of positive and negative valence are altered in patients with anxiety disorders. However, neural coding of both anxiety and valence by IC neurons remains unknown. Using fiber photometry recordings in mice, we uncover a selective increase of activity in IC projection neurons of the anterior (aIC), but not posterior (pIC) section, when animals are exploring anxiogenic spaces, and this activity is proportional to the level of anxiety of mice. Neurons in aIC also respond to stimuli of positive and negative valence, and the strength of response to strong negative stimuli is proportional to mice levels of anxiety. Using ex vivo electrophysiology, we characterized the IC connection to the basolateral amygdala (BLA), and employed projection-specific optogenetics to reveal anxiogenic properties of aIC-BLA neurons. Finally, we identified that aIC-BLA neurons are activated in anxiogenic spaces, as well as in response to aversive stimuli, and that both activities are positively correlated. Altogether, we identified a common neurobiological substrate linking negative valence with anxiety-related information and behaviors, which provides a starting point to understand how alterations of these neural populations contribute to psychiatric disorders.

Abstract:
Corticosteroid-mediated stress responses require the activation of complex brain circuits involving mitochondrial activity, but the underlying cellular and molecular mechanisms are scantly known. The endocannabinoid system is implicated in stress coping, and it can directly regulate brain mitochondrial functions via type 1 cannabinoid (CB(1)) receptors associated with mitochondrial membranes (mtCB(1)). In this study, we show that the impairing effect of corticosterone in the novel object recognition (NOR) task in mice requires mtCB(1) receptors and the regulation of mitochondrial calcium levels in neurons. Different brain circuits are modulated by this mechanism to mediate the impact of corticosterone during specific phases of the task. Thus, whereas corticosterone recruits mtCB(1) receptors in noradrenergic neurons to impair NOR consolidation, mtCB(1) receptors in local hippocampal GABAergic interneurons are required to inhibit NOR retrieval. These data reveal unforeseen mechanisms mediating the effects of corticosteroids during different phases of NOR, involving mitochondrial calcium alterations in different brain circuits.

Abstract:

Abstract:
Intracellular calcium signaling underlies the astroglial control of synaptic transmission and plasticity. Mitochondria-endoplasmic reticulum contacts (MERCs) are key determinants of calcium dynamics, but their functional impact on astroglial regulation of brain information processing is unexplored. We found that the activation of astrocyte mitochondrial-associated type-1 cannabinoid (mtCB(1)) receptors determines MERC-dependent intracellular calcium signaling and synaptic integration. The stimulation of mtCB(1) receptors promotes calcium transfer from the endoplasmic reticulum to mitochondria through a specific molecular cascade, involving the mitochondrial calcium uniporter (MCU). Physiologically, mtCB(1)-dependent mitochondrial calcium uptake determines the dynamics of cytosolic calcium events in astrocytes upon endocannabinoid mobilization. Accordingly, electrophysiological recordings in hippocampal slices showed that conditional genetic exclusion of mtCB(1) receptors or dominant-negative MCU expression in astrocytes blocks lateral synaptic potentiation, through which astrocytes integrate the activity of distant synapses. Altogether, these data reveal an endocannabinoid link between astroglial MERCs and the regulation of brain network functions.

Abstract:
Recent advances in medications for neurodegenerative disorders are expanding opportunities for improving the debilitating symptoms suffered by patients. Existing pharmacologic treatments, however, often rely on systemic drug administration, which result in broad drug distribution and consequent increased risk for toxicity. Given that many key neural circuitries have sub-cubic millimeter volumes and cell-specific characteristics, small-volume drug administration into affected brain areas with minimal diffusion and leakage is essential. We report the development of an implantable, remotely controllable, miniaturized neural drug delivery system permitting dynamic adjustment of therapy with pinpoint spatial accuracy. We demonstrate that this device can chemically modulate local neuronal activity in small (rodent) and large (nonhuman primate) animal models, while simultaneously allowing the recording of neural activity to enable feedback control.

Abstract:
Understanding the neural mechanisms underlying human cognition and determining the causal factors for the development of brain pathologies are among the greatest challenges for society. Electrophysiological recordings offer remarkable observations of brain activity as they provide highly precise representations of information coding in both temporal and spatial domains. With the development of genetic tools over the last decades, mice have been a key model organism in neuroscience. However, conducting chronic in vivo electrophysiology in awake, behaving mice remains technically challenging, and this difficulty prevents many research teams from acquiring critical recordings in their mouse models. Behavioral training, implant fabrication, brain surgery, data acquisition and data analysis are all required steps that must be mastered in order to perform cutting-edge experiments in systems neuroscience. Here, we present a new method that simplifies the construction of a drivable and multi-task electrophysiological recording implant without loss of flexibility and recording power. The hybrid-drive combining optogenetics, pharmacology and electrophysiology (HOPE) can support up to 16 tetrodes, attached to a single drive mechanism, organized in two bundles of eight tetrodes, allowing recordings in two different mouse brain regions simultaneously with two optical fibers for optogenetic manipulation or two injection cannulas for drug-delivery experiments. Because it can be printed with a latest-generation desktop 3D printer, the production cost is low compared to classical electrophysiology implants, and it can be built within a few hours. The HOPE implant is also reconfigurable to specific needs as it has been created in a computer-aided design (CAD) software and all the files used for its construction are open-source.

Abstract:
Effective evaluation of costs and benefits is a core survival capacity that in humans is considered as optimal, 'rational' decision-making. This capacity is vulnerable in neuropsychiatric disorders and in the aftermath of chronic stress, in which aberrant choices and high-risk behaviors occur. We report that chronic stress exposure in rodents produces abnormal evaluation of costs and benefits resembling non-optimal decision-making in which choices of high-cost/high-reward options are sharply increased. Concomitantly, alterations in the task-related spike activity of medial prefrontal neurons correspond with increased activity of their striosome-predominant striatal projection neuron targets and with decreased and delayed striatal fast-firing interneuron activity. These effects of chronic stress on prefronto-striatal circuit dynamics could be blocked or be mimicked by selective optogenetic manipulation of these circuits. We suggest that altered excitation-inhibition dynamics of striosome-based circuit function could be an underlying mechanism by which chronic stress contributes to disorders characterized by aberrant decision-making under conflict. VIDEO ABSTRACT.

Abstract:
The hippocampus is important for contextual behavior, and the striatum plays key roles in decision making. When studying the functional relationships with the hippocampus, prior studies have focused mostly on the dorsolateral striatum (DLS), emphasizing the antagonistic relationships between the hippocampus and DLS in spatial versus response learning. By contrast, the functional relationships between the dorsomedial striatum (DMS) and hippocampus are relatively unknown. The current study reports that lesions to both the hippocampus and DMS profoundly impaired performance of rats in a visual scene-based memory task in which the animals were required to make a choice response by using visual scenes displayed in the background. Analysis of simultaneous recordings of local field potentials revealed that the gamma oscillatory power was higher in the DMS, but not in CA1, when the rat performed the task using familiar scenes than novel ones. In addition, the CA1-DMS networks increased coherence at gamma, but not at theta, rhythm as the rat mastered the task. At the single-unit level, the neuronal populations in CA1 and DMS showed differential firing patterns when responses were made using familiar visual scenes than novel ones. Such learning-dependent firing patterns were observed earlier in the DMS than in CA1 before the rat made choice responses. The present findings suggest that both the hippocampus and DMS process memory representations for visual scenes in parallel with different time courses and that flexible choice action using background visual scenes requires coordinated operations of the hippocampus and DMS at gamma frequencies.

Abstract:
We tested single APP (Tg2576) transgenic, PS1 (PS1dE9) transgenic, and double APP/PS1 transgenic mice at 3 and 6 months of age on the acquisition of a hippocampal-dependent operant 'differential reinforcement of low rate schedule' (DRL) paradigm. In this task mice are required to wait for at least 10 seconds (DRL-10s) between 2 consecutive nose poke responses. Our data showed that while single APP and PS1 transgene expression did not affect DRL learning and performance, mice expressing double APP/PS1 transgenes were impaired in the acquisition of DRL-10s at 6 months, but not at 3 months of age. The same impaired double transgenic mice, however, were perfectly capable of normal acquisition of signaled DRL-10s (SDRL-10s) task, a hippocampal-independent task, wherein mice were required to emit responses when the end of the 10-second delay was signaled by a lighting of the chamber. The age-dependent and early deficits of APP/PS1 mice suggest that the appetitive DRL paradigm is sensitive to the amyloid pathology present in double APP/PS1 mice, and that this mouse line represents a good model with which to study the efficacy of therapeutic strategies against Alzheimer's disease.

Abstract:
Hippocampus and prefrontal cortex (PFC) process spatiotemporally discrete events while maintaining goal-directed task demands. Although some studies have reported that neural activities in the two regions are coordinated, such observations have rarely been reported in an object-place paired-associate (OPPA) task in which animals must learn an object-in-place rule. In this study, we recorded single units and local field potentials simultaneously from the CA1 subfield of the hippocampus and PFC as rats learned that Object A, but not Object B, was rewarded in Place 1, but not in Place 2 (vice versa for Object B). Both hippocampus and PFC are required for normal performance in this task. PFC neurons fired in association with the regularity of the occurrence of a certain type of event independent of space, whereas neuronal firing in CA1 was spatially localized for representing a discrete place. Importantly, the differential firing patterns were observed in tandem with common learning-related changes in both regions. Specifically, once OPPA learning occurred and rats used an object-in-place strategy, (1) both CA1 and PFC neurons exhibited spatially more similar and temporally more synchronized firing patterns, (2) spiking activities in both regions were more phase locked to theta rhythms, and (3) CA1-medial PFC coherence in theta oscillation was maximal before entering a critical place for decision making. The results demonstrate differential as well as common neural dynamics between hippocampus and PFC in acquiring the OPPA task and strongly suggest that both regions form a unified functional network for processing an episodic event.