Distinct role of nucleus accumbens D2-MSN projections to ventral pallidum in different phases of motivated behavior.

The nucleus accumbens (NAc) is a key region in motivated behaviors. NAc medium spiny neurons (MSNs) are divided into those expressing dopamine receptor D1 or D2. Classically, D1- and D2-MSNs have been described as having opposing roles in reinforcement, but recent evidence suggests a more complex role for D2-MSNs. Here, we show that optogenetic modulation of D2-MSN to ventral pallidum (VP) projections during different stages of motivated behavior has contrasting effects in motivation. Activation of D2-MSN-VP projections during a reward-predicting cue results in increased motivational drive, whereas activation at reward delivery decreases motivation; optical inhibition triggers the opposite behavioral effect. In addition, in a free-choice instrumental task, animals prefer the lever that originates one pellet in opposition to pellet plus D2-MSN-VP optogenetic activation and vice versa for optogenetic inhibition. In summary, D2-MSN-VP projections play different, and even opposing, roles in distinct phases of motivated behavior.

Signatures of brain criticality unveiled by maximum entropy analysis across cortical states.

It has recently been reported that statistical signatures of brain criticality, obtained from distributions of neuronal avalanches, can depend on the cortical state. We revisit these claims with a completely different and independent approach, employing a maximum entropy model to test whether signatures of criticality appear in urethane-anesthetized rats. To account for the spontaneous variation of cortical states, we parse the time series and perform the maximum entropy analysis as a function of the variability of the population spiking activity. To compare data sets with different numbers of neurons, we define a normalized distance to criticality that takes into account the peak and width of the specific heat curve. We found a universal collapse of the normalized distance to criticality dependence on the cortical state, on an animal by animal basis. This indicates a universal dynamics and a critical point at an intermediate value of spiking variability.

Correction: Nucleus accumbens medium spiny neurons subtypes signal both reward and aversion.

A correction to this paper has been published and can be accessed via a link at the top of the paper.

Nucleus accumbens medium spiny neurons subtypes signal both reward and aversion.

Deficits in decoding rewarding (and aversive) signals are present in several neuropsychiatric conditions such as depression and addiction, emphasising the importance of studying the underlying neural circuits in detail. One of the key regions of the reward circuit is the nucleus accumbens (NAc). The classical view on the field postulates that NAc dopamine receptor D1-expressing medium spiny neurons (D1-MSNs) convey reward signals, while dopamine receptor D2-expressing MSNs (D2-MSNs) encode aversion. Here, we show that both MSN subpopulations can drive reward and aversion, depending on their neuronal stimulation pattern. Brief D1- or D2-MSN optogenetic stimulation elicited positive reinforcement and enhanced cocaine conditioning. Conversely, prolonged activation induced aversion, and in the case of D2-MSNs, decreased cocaine conditioning. Brief stimulation was associated with increased ventral tegmenta area (VTA) dopaminergic tone either directly (for D1-MSNs) or indirectly via ventral pallidum (VP) (for D1- and D2-MSNs). Importantly, prolonged stimulation of either MSN subpopulation induced remarkably distinct electrophysiological effects in these target regions. We further show that blocking κ-opioid receptors in the VTA (but not in VP) abolishes the behavioral effects induced by D1-MSN prolonged stimulation. In turn, blocking δ-opioid receptors in the VP (but not in VTA) blocks the behavioral effects elicited by D2-MSN prolonged stimulation. Our findings demonstrate that D1- and D2-MSNs can bidirectionally control reward and aversion, explaining the existence of controversial studies in the field, and highlights that the proposed striatal functional opposition needs to be reconsidered.

Subsampled Directed-Percolation Models Explain Scaling Relations Experimentally Observed in the Brain.

Recent experimental results on spike avalanches measured in the urethane-anesthetized rat cortex have revealed scaling relations that indicate a phase transition at a specific level of cortical firing rate variability. The scaling relations point to critical exponents whose values differ from those of a branching process, which has been the canonical model employed to understand brain criticality. This suggested that a different model, with a different phase transition, might be required to explain the data. Here we show that this is not necessarily the case. By employing two different models belonging to the same universality class as the branching process (mean-field directed percolation) and treating the simulation data exactly like experimental data, we reproduce most of the experimental results. We find that subsampling the model and adjusting the time bin used to define avalanches (as done with experimental data) are sufficient ingredients to change the apparent exponents of the critical point. Moreover, experimental data is only reproduced within a very narrow range in parameter space around the phase transition.

Low-cost open hardware system for behavioural experiments simultaneously with electrophysiological recordings.

A major frontier in neuroscience is to find neural correlates of perception, learning, decision making, and a variety of other types of behavior. In the last decades, modern devices allow simultaneous recordings of different operant responses and the electrical activity of large neuronal populations. However, the commercially available instruments for studying operant conditioning are expensive, and the design of low-cost chambers has emerged as an appealing alternative to resource-limited laboratories engaged in animal behavior. In this article, we provide a full description of a platform that records the operant behavior and synchronizes it with the electrophysiological activity. The programming of this platform is open source, flexible, and adaptable to a wide range of operant conditioning tasks. We also show results of operant conditioning experiments with freely moving rats with simultaneous electrophysiological recordings.

Role of laterodorsal tegmentum projections to nucleus accumbens in reward-related behaviors.

The laterodorsal tegmentum (LDT) is associated with reward considering that it modulates VTA neuronal activity, but recent anatomical evidence shows that the LDT also directly projects to nucleus accumbens (NAc). We show that the majority of LDT-NAc inputs are cholinergic, but there is also GABAergic and glutamatergic innervation; activation of LDT induces a predominantly excitatory response in the NAc. Non-selective optogenetic activation of LDT-NAc projections in rats enhances motivational drive and shifts preference to an otherwise equal reward; whereas inhibition of these projections induces the opposite. Activation of these projections also induces robust place preference. In mice, specific activation of LDT-NAc cholinergic inputs (but not glutamatergic or GABAergic) is sufficient to shift preference, increase motivation, and drive positive reinforcement in different behavioral paradigms. These results provide evidence that LDT-NAc projections play an important role in motivated behaviors and positive reinforcement, and that distinct neuronal populations differentially contribute for these behaviors.

Criticality between Cortical States.

Since the first measurements of neuronal avalanches, the critical brain hypothesis has gained traction. However, if the brain is critical, what is the phase transition? For several decades, it has been known that the cerebral cortex operates in a diversity of regimes, ranging from highly synchronous states (with higher spiking variability) to desynchronized states (with lower spiking variability). Here, using both new and publicly available data, we test independent signatures of criticality and show that a phase transition occurs in an intermediate value of spiking variability, in both anesthetized and freely moving animals. The critical exponents point to a universality class different from mean-field directed percolation. Importantly, as the cortex hovers around this critical point, the avalanche exponents follow a linear relation that encompasses previous experimental results from different setups and is reproduced by a model.

Coupled variability in primary sensory areas and the hippocampus during spontaneous activity.

The cerebral cortex is an anatomically divided and functionally specialized structure. It includes distinct areas, which work on different states over time. The structural features of spiking activity in sensory cortices have been characterized during spontaneous and evoked activity. However, the coordination among cortical and sub-cortical neurons during spontaneous activity across different states remains poorly characterized. We addressed this issue by studying the temporal coupling of spiking variability recorded from primary sensory cortices and hippocampus of anesthetized or freely behaving rats. During spontaneous activity, spiking variability was highly correlated across primary cortical sensory areas at both small and large spatial scales, whereas the cortico-hippocampal correlation was modest. This general pattern of spiking variability was observed under urethane anesthesia, as well as during waking, slow-wave sleep and rapid-eye-movement sleep, and was unchanged by novel stimulation. These results support the notion that primary sensory areas are strongly coupled during spontaneous activity.

An investigation of Hebbian phase sequences as assembly graphs.

Hebb proposed that synapses between neurons that fire synchronously are strengthened, forming cell assemblies and phase sequences. The former, on a shorter scale, are ensembles of synchronized cells that function transiently as a closed processing system; the latter, on a larger scale, correspond to the sequential activation of cell assemblies able to represent percepts and behaviors. Nowadays, the recording of large neuronal populations allows for the detection of multiple cell assemblies. Within Hebb's theory, the next logical step is the analysis of phase sequences. Here we detected phase sequences as consecutive assembly activation patterns, and then analyzed their graph attributes in relation to behavior. We investigated action potentials recorded from the adult rat hippocampus and neocortex before, during and after novel object exploration (experimental periods). Within assembly graphs, each assembly corresponded to a node, and each edge corresponded to the temporal sequence of consecutive node activations. The sum of all assembly activations was proportional to firing rates, but the activity of individual assemblies was not. Assembly repertoire was stable across experimental periods, suggesting that novel experience does not create new assemblies in the adult rat. Assembly graph attributes, on the other hand, varied significantly across behavioral states and experimental periods, and were separable enough to correctly classify experimental periods (Naïve Bayes classifier; maximum AUROCs ranging from 0.55 to 0.99) and behavioral states (waking, slow wave sleep, and rapid eye movement sleep; maximum AUROCs ranging from 0.64 to 0.98). Our findings agree with Hebb's view that assemblies correspond to primitive building blocks of representation, nearly unchanged in the adult, while phase sequences are labile across behavioral states and change after novel experience. The results are compatible with a role for phase sequences in behavior and cognition.

Speech graphs provide a quantitative measure of thought disorder in psychosis.

BACKGROUND: Psychosis has various causes, including mania and schizophrenia. Since the differential diagnosis of psychosis is exclusively based on subjective assessments of oral interviews with patients, an objective quantification of the speech disturbances that characterize mania and schizophrenia is in order. In principle, such quantification could be achieved by the analysis of speech graphs. A graph represents a network with nodes connected by edges; in speech graphs, nodes correspond to words and edges correspond to semantic and grammatical relationships. METHODOLOGY/PRINCIPAL FINDINGS: To quantify speech differences related to psychosis, interviews with schizophrenics, manics and normal subjects were recorded and represented as graphs. Manics scored significantly higher than schizophrenics in ten graph measures. Psychopathological symptoms such as logorrhea, poor speech, and flight of thoughts were grasped by the analysis even when verbosity differences were discounted. Binary classifiers based on speech graph measures sorted schizophrenics from manics with up to 93.8% of sensitivity and 93.7% of specificity. In contrast, sorting based on the scores of two standard psychiatric scales (BPRS and PANSS) reached only 62.5% of sensitivity and specificity. CONCLUSIONS/SIGNIFICANCE: The results demonstrate that alterations of the thought process manifested in the speech of psychotic patients can be objectively measured using graph-theoretical tools, developed to capture specific features of the normal and dysfunctional flow of thought, such as divergence and recurrence. The quantitative analysis of speech graphs is not redundant with standard psychometric scales but rather complementary, as it yields a very accurate sorting of schizophrenics and manics. Overall, the results point to automated psychiatric diagnosis based not on what is said, but on how it is said.