How Dopamine Enables Learning from Aversion.

Dopamine is heavily studied for its role in reward learning, but it is becoming increasingly appreciated that dopamine can also enable learning from aversion. Dopamine neurons modulate their firing and neurotransmitter release patterns in response to aversive outcomes. However, there is considerable heterogeneity in the timing and directionality of the modulation.

Dopamine across timescales and cell types: Relevance for phenotypes in Parkinson's disease progression.

Dopamine neurons in the substantia nigra pars compacta (SNc) synthesize and release dopamine, a critical neurotransmitter for movement and learning. SNc dopamine neurons degenerate in Parkinson's Disease (PD), causing a host of motor and non-motor symptoms. Here, we review recent conceptual advances in our basic understanding of the dopamine system - including our rapidly advancing knowledge of dopamine neuron heterogeneity - with special attention to their importance for understanding PD.

Hidden variables in stress neurobiology research.

Among the central goals of stress neurobiology research is to understand the mechanisms by which stressors change neural circuit function to precipitate or exacerbate psychiatric symptoms. Yet despite decades of effort, psychiatric medications that target the biological substrates of the stress response are largely lacking. We propose that the clinical advancement of stress response-based therapeutics for psychiatric disorders may be hindered by 'hidden variables' in stress research, including considerations of behavioral study design (stressors and outcome measures), individual variability, sex differences, and the interaction of the body's stress hormone system with endogenous circadian and ultradian rhythms.

Chronically dysregulated corticosterone impairs dopaminergic transmission in the dorsomedial striatum by sex-divergent mechanisms.

Major depressive disorder (MDD) is a leading cause of disability worldwide. Individuals with MDD exhibit decreased motivation and deficits in reward processing. In a subset of MDD patients, chronic dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis occurs, resulting in increased levels of the 'stress hormone' cortisol during the normal rest period (i.

Striatonigrostriatal circuit architecture for disinhibition of dopamine signaling.

The basal ganglia operate largely in closed parallel loops, including an associative circuit for goal-directed behavior originating from the dorsomedial striatum (DMS) and a somatosensory circuit important for habit formation originating from the dorsolateral striatum (DLS). An exception to this parallel circuit organization has been proposed to explain how information might be transferred between striatal subregions, for example, from the DMS to the DLS during habit formation. The "ascending spiral hypothesis" proposes that the DMS disinhibits dopamine signaling in the DLS through a tri-synaptic, open-loop striatonigrostriatal circuit.

Dopamine signaling in the dorsomedial striatum promotes compulsive behavior.

Compulsive behavior is a defining feature of disorders such as substance use disorders. Current evidence suggests that corticostriatal circuits control the expression of established compulsions, but little is known about the mechanisms regulating the development of compulsions. We hypothesized that dopamine, a critical modulator of striatal synaptic plasticity, could control alterations in corticostriatal circuits leading to the development of compulsions (defined here as continued reward seeking in the face of punishment).

GuPPy, a Python toolbox for the analysis of fiber photometry data.

Fiber photometry (FP) is an adaptable method for recording in vivo neural activity in freely behaving animals. It has become a popular tool in neuroscience due to its ease of use, low cost, the ability to combine FP with freely moving behavior, among other advantages. However, analysis of FP data can be challenging for new users, especially those with a limited programming background.

Dopamine, Updated: Reward Prediction Error and Beyond.

Dopamine neurons have been intensely studied for their roles in reinforcement learning. A dominant theory of how these neurons contribute to learning is through the encoding of a reward prediction error (RPE) signal. Recent advances in dopamine research have added nuance to RPE theory by incorporating the ideas of sensory prediction error, distributional encoding, and belief states.

Parvalbumin and Npas1 Pallidal Neurons Have Distinct Circuit Topology and Function.

The external globus pallidus (GPe) is a critical node within the basal ganglia circuit. Phasic changes in the activity of GPe neurons during movement and their alterations in Parkinson's disease (PD) argue that the GPe is important in motor control. Parvalbumin-positive (PV) neurons and Npas1 neurons are the two principal neuron classes in the GPe.

Amygdala-Midbrain Connections Modulate Appetitive and Aversive Learning.

The central amygdala (CeA) orchestrates adaptive responses to emotional events. While CeA substrates for defensive behaviors have been studied extensively, CeA circuits for appetitive behaviors and their relationship to threat-responsive circuits remain poorly defined. Here, we demonstrate that the CeA sends robust inhibitory projections to the lateral substantia nigra (SNL) that contribute to appetitive and aversive learning in mice.

Interfacing behavioral and neural circuit models for habit formation.

Habits are an important mechanism by which organisms can automate the control of behavior to alleviate cognitive demand. However, transitions to habitual control are risky because they lead to inflexible responding in the face of change. The question of how the brain controls transitions into habit is thus an intriguing one.

The cerebellum shows its stripes.

New studies examine how the different sub-structures in the cerebellum are organized to receive information during complex behavioral tasks.

Neuronal Dynamics Regulating Brain and Behavioral State Transitions.

Prolonged behavioral challenges can cause animals to switch from active to passive coping strategies to manage effort-expenditure during stress; such normally adaptive behavioral state transitions can become maladaptive in psychiatric disorders such as depression. The underlying neuronal dynamics and brainwide interactions important for passive coping have remained unclear. Here, we develop a paradigm to study these behavioral state transitions at cellular-resolution across the entire vertebrate brain.

A dLight-ful New View of Neuromodulation.

Neuromodulators such as dopamine can transform neural circuit function, but the mechanisms underlying such transformations are incompletely understood. A recent study introduced dLight1, a genetically encoded fluorescent dopamine indicator. dLight1 allows the optical measurement of dopamine sensed by isolated target circuits with high spatiotemporal resolution and has unique advantages for the study of neuromodulatory mechanisms.

Nucleus accumbens D2R cells signal prior outcomes and control risky decision-making.

A marked bias towards risk aversion has been observed in nearly every species tested. A minority of individuals, however, instead seem to prefer risk (repeatedly choosing uncertain large rewards over certain but smaller rewards), and even risk-averse individuals sometimes opt for riskier alternatives. It is not known how neural activity underlies such important shifts in decision-making--either as a stable trait across individuals or at the level of variability within individuals.

Communication in Neural Circuits: Tools, Opportunities, and Challenges.

Communication, the effective delivery of information, is fundamental to life across all scales and species. Nervous systems (by necessity) may be most specifically adapted among biological tissues for high rate and complexity of information transmitted, and thus, the properties of neural tissue and principles of its organization into circuits may illuminate capabilities and limitations of biological communication. Here, we consider recent developments in tools for studying neural circuits with particular attention to defining neuronal cell types by input and output information streams--i.

Simultaneous fast measurement of circuit dynamics at multiple sites across the mammalian brain.

Real-time activity measurements from multiple specific cell populations and projections are likely to be important for understanding the brain as a dynamical system. Here we developed frame-projected independent-fiber photometry (FIP), which we used to record fluorescence activity signals from many brain regions simultaneously in freely behaving mice. We explored the versatility of the FIP microscope by quantifying real-time activity relationships among many brain regions during social behavior, simultaneously recording activity along multiple axonal pathways during sensory experience, performing simultaneous two-color activity recording, and applying optical perturbation tuned to elicit dynamics that match naturally occurring patterns observed during behavior.

Basomedial amygdala mediates top-down control of anxiety and fear.

Anxiety-related conditions are among the most difficult neuropsychiatric diseases to treat pharmacologically, but respond to cognitive therapies. There has therefore been interest in identifying relevant top-down pathways from cognitive control regions in medial prefrontal cortex (mPFC). Identification of such pathways could contribute to our understanding of the cognitive regulation of affect, and provide pathways for intervention.

Intact-Brain Analyses Reveal Distinct Information Carried by SNc Dopamine Subcircuits.

Recent progress in understanding the diversity of midbrain dopamine neurons has highlighted the importance--and the challenges--of defining mammalian neuronal cell types. Although neurons may be best categorized using inclusive criteria spanning biophysical properties, wiring of inputs, wiring of outputs, and activity during behavior, linking all of these measurements to cell types within the intact brains of living mammals has been difficult. Here, using an array of intact-brain circuit interrogation tools, including CLARITY, COLM, optogenetics, viral tracing, and fiber photometry, we explore the diversity of dopamine neurons within the substantia nigra pars compacta (SNc).

Frequency-dependent, cell type-divergent signaling in the hippocamposeptal projection.

Hippocampal oscillations are critical for information processing, and are strongly influenced by inputs from the medial septum. Hippocamposeptal neurons provide direct inhibitory feedback from the hippocampus onto septal cells, and are therefore likely to also play an important role in the circuit; these neurons fire at either low or high frequency, reflecting hippocampal network activity during theta oscillations or ripple events, respectively. Here, we optogenetically target the long-range GABAergic projection from the hippocampus to the medial septum in rats, and thereby simulate hippocampal input onto downstream septal cells in an acute slice preparation.