The microcircuits of striatum in silico.

The basal ganglia play an important role in decision making and selection of action primarily based on input from cortex, thalamus, and the dopamine system. Their main input structure, striatum, is central to this process. It consists of two types of projection neurons, together representing 95% of the neurons, and 5% of interneurons, among which are the cholinergic, fast-spiking, and low threshold-spiking subtypes. The membrane properties, soma-dendritic shape, and intrastriatal and extrastriatal synaptic interactions of these neurons are quite well described in the mouse, and therefore they can be simulated in sufficient detail to capture their intrinsic properties, as well as the connectivity. We focus on simulation at the striatal cellular/microcircuit level, in which the molecular/subcellular and systems levels meet. We present a nearly full-scale model of the mouse striatum using available data on synaptic connectivity, cellular morphology, and electrophysiological properties to create a microcircuit mimicking the real network. A striatal volume is populated with reconstructed neuronal morphologies with appropriate cell densities, and then we connect neurons together based on appositions between neurites as possible synapses and constrain them further with available connectivity data. Moreover, we simulate a subset of the striatum involving 10,000 neurons, with input from cortex, thalamus, and the dopamine system, as a proof of principle. Simulation at this biological scale should serve as an invaluable tool to understand the mode of operation of this complex structure. This platform will be updated with new data and expanded to simulate the entire striatum.

The Functional Organization of Cortical and Thalamic Inputs onto Five Types of Striatal Neurons Is Determined by Source and Target Cell Identities.

To understand striatal function, it is essential to know the functional organization of the numerous inputs targeting the diverse population of striatal neurons. Using optogenetics, we activated terminals from ipsi- or contralateral primary somatosensory cortex (S1) or primary motor cortex (M1), or thalamus while obtaining simultaneous whole-cell recordings from pairs or triplets of striatal medium spiny neurons (MSNs) and adjacent interneurons. Ipsilateral corticostriatal projections provided stronger excitation to fast-spiking interneurons (FSIs) than to MSNs and only sparse and weak excitation to low threshold-spiking interneurons (LTSIs) and cholinergic interneurons (ChINs). Projections from contralateral M1 evoked the strongest responses in LTSIs but none in ChINs, whereas thalamus provided the strongest excitation to ChINs but none to LTSIs. In addition, inputs varied in their glutamate receptor composition and their short-term plasticity. Our data revealed a highly selective organization of excitatory striatal afferents, which is determined by both pre- and postsynaptic neuronal identity.

A hypothalamus-habenula circuit controls aversion.

Encoding and predicting aversive events are critical functions of circuits that support survival and emotional well-being. Maladaptive circuit changes in emotional valence processing can underlie the pathophysiology of affective disorders. The lateral habenula (LHb) has been linked to aversion and mood regulation through modulation of the dopamine and serotonin systems. We have defined the identity and function of glutamatergic (Vglut2) control of the LHb, comparing the role of inputs originating in the globus pallidus internal segment (GPi), and lateral hypothalamic area (LHA), respectively. We found that LHb-projecting LHA neurons, and not the proposed GABA/glutamate co-releasing GPi neurons, are responsible for encoding negative value. Monosynaptic rabies tracing of the presynaptic organization revealed a predominantly limbic input onto LHA Vglut2 neurons, while sensorimotor inputs were more prominent onto GABA/glutamate co-releasing GPi neurons. We further recorded the activity of LHA Vglut2 neurons, by imaging calcium dynamics in response to appetitive versus aversive events in conditioning paradigms. LHA Vglut2 neurons formed activity clusters representing distinct reward or aversion signals, including a population that responded to mild foot shocks and predicted aversive events. We found that the LHb-projecting LHA Vglut2 neurons encode negative valence and rapidly develop a prediction signal for negative events. These findings establish the glutamatergic LHA-LHb circuit as a critical node in value processing.

Delirium in older hospitalized patients-signs and actions: a retrospective patient record review.

BACKGROUND: Delirium is common in older hospitalized patients, and is associated with negative consequences for the patients, next of kin, healthcare professionals and healthcare costs. It is important to understand its clinical features, as almost 40% of all cases in hospitals may be preventable. Yet, delirium in hospitalized patients is often unrecognized and untreated. Few studies describe thoroughly how delirium manifests itself in older hospitalized patients and what actions healthcare professionals take in relation to these signs. Therefore, the aim of this study was to describe signs of delirium in older hospitalized patients and action taken by healthcare professionals, as reported in patient records. METHODS: Patient records from patients aged ≥65 (n = 286) were retrospectively reviewed for signs of delirium, which was found in 78 patient records (27%). Additionally, these records were reviewed for action taken by healthcare professionals in relation to the patients' signs of delirium. The identified text was analyzed with qualitative content analysis in two steps. RESULTS: Healthcare professionals responded only in part to older hospitalized patients' needs of care in relation to their signs of delirium. The patients displayed various signs of delirium that led to a reduced ability to participate in their own care and to keep themselves free from harm. Healthcare professionals met these signs with a variation of actions and the care was adapted, deficient and beyond the usual care. A systematic and holistic perspective in the care of older hospitalized patients with signs of delirium was missing. CONCLUSION: Improved knowledge about delirium in hospitals is needed in order to reduce human suffering, healthcare utilization and costs. It is important to enable older hospitalized patients with signs of delirium to participate in their own care and to protect them from harm. Delirium has to be seen as a preventable adverse event in all hospitals units. To improve the prevention and management of older hospitalized patients with signs of delirium, person-centered care and patient safety may be important issues.