The Insular Cortex: An Interface Between Sensation, Emotion and Cognition.

The insula is a complex brain region central to the orchestration of taste perception, interoception, emotion, and decision-making. Recent research has shed light on the intricate connections between the insula and other brain regions, revealing the crucial role of this area in integrating sensory, emotional, and cognitive information. The unique anatomical position and extensive connectivity allow the insula to serve as a critical hub in the functional network of the brain. We summarize its role in interoceptive and exteroceptive sensory processing, illustrating insular function as a bridge connecting internal and external experiences. Drawing on recent research, we delineate the insular involvement in emotional processes, highlighting its implications in psychiatric conditions, such as anxiety, depression, and addiction. We further discuss the insular contributions to cognition, focusing on its significant roles in time perception and decision-making. Collectively, the evidence underscores the insular function as a dynamic interface that synthesizes diverse inputs into coherent subjective experiences and decision-making processes. Through this review, we hope to highlight the importance of the insula as an interface between sensation, emotion, and cognition, and to inspire further research into this fascinating brain region.

A genetically defined insula-brainstem circuit selectively controls motivational vigor.

The anterior insular cortex (aIC) plays a critical role in cognitive and motivational control of behavior, but the underlying neural mechanism remains elusive. Here, we show that aIC neurons expressing Fezf2 (aICFezf2), which are the pyramidal tract neurons, signal motivational vigor and invigorate need-seeking behavior through projections to the brainstem nucleus tractus solitarii (NTS). aICFezf2 neurons and their postsynaptic NTS neurons acquire anticipatory activity through learning, which encodes the perceived value and the vigor of actions to pursue homeostatic needs. Correspondingly, aIC → NTS circuit activity controls vigor, effort, and striatal dopamine release but only if the action is learned and the outcome is needed. Notably, aICFezf2 neurons do not represent taste or valence. Moreover, aIC → NTS activity neither drives reinforcement nor influences total consumption. These results pinpoint specific functions of aIC → NTS circuit for selectively controlling motivational vigor and suggest that motivation is subserved, in part, by aIC's top-down regulation of dopamine signaling.

A Genetically Defined Compartmentalized Striatal Direct Pathway for Negative Reinforcement.

The striosome compartment within the dorsal striatum has been implicated in reinforcement learning and regulation of motivation, but how striosomal neurons contribute to these functions remains elusive. Here, we show that a genetically identified striosomal population, which expresses the Teashirt family zinc finger 1 (Tshz1) and belongs to the direct pathway, drives negative reinforcement and is essential for aversive learning in mice. Contrasting a "conventional" striosomal direct pathway, the Tshz1 neurons cause aversion, movement suppression, and negative reinforcement once activated, and they receive a distinct set of synaptic inputs. These neurons are predominantly excited by punishment rather than reward and represent the anticipation of punishment or the motivation for avoidance. Furthermore, inhibiting these neurons impairs punishment-based learning without affecting reward learning or movement. These results establish a major role of striosomal neurons in behaviors reinforced by punishment and moreover uncover functions of the direct pathway unaccounted for in classic models.

Persistent Neuronal Activity in Anterior Cingulate Cortex Correlates with Sustained Attention in Rats Regardless of Sensory Modality.

The anterior cingulate cortex (ACC) has long been thought to regulate conflict between an object of attention and distractors during goal-directed sustained attention. However, it is unclear whether ACC serves to sustained attention itself. Here, we developed a task in which the time course of sustained attention could be controlled in rats. Then, using pharmacological lesion experiments, we employed it to assess function of ACC in sustained attention. We then recorded neuronal activity in ACC using multichannel extracellular recording techniques and identified specific ACC neurons persistently activated during the period of attention. Further experiments showed that target modality had minimal influence on the neuronal activity, and distracting external sensory input during the attention period did not perturb persistent neuronal activity. Additionally, minimal trial-to-trial variability in neuronal activity observed during sustained attention supports a role for ACC neurons in that behavior. Therefore, we conclude that the ACC neuronal activity correlates with sustained attention.

Periaqueductal Gray Neuronal Activities Underlie Different Aspects of Defensive Behaviors.

UNLABELLED: Defense is a basic survival mechanism when animals face danger. Previous studies have suggested that the midbrain periaqueductal gray (PAG) is essential for the generation of defensive reactions. Here we showed that optogenetic activation of neurons in the PAG in mice was sufficient to induce a series of defensive responses (including running, freezing, and avoidance). However, the endogenous neural dynamics of the PAG underlying defensive behaviors still remain elusive. Using chronic extracellular recording, we recorded the spiking activities of PAG neurons in freely behaving mice exposed to natural threats (rats). We observed that there exist distinct neuronal subsets within the PAG participating in respective detection (risk assessment) and response (flight) aspects of defensive behaviors. Our results demonstrate the important role of PAG neuronal activities in the control of different aspects of defensive behaviors, and provide novel insights for investigating defense from an electrophysiological perspective. SIGNIFICANCE STATEMENT: Defense is crucial for animals' survival in nature. Here, using optogenetic stimulation and in vivo recording in behaving mice reacting to threats, we explored the role of the midbrain periaqueductal gray (PAG) in defense. We show that optogenetic activation of PAG neurons is sufficient to elicit different aspects of defensive responses. Consistently, the present study provides in vivo evidence demonstrating that activity of the population of dorsal PAG neurons is activated during defense. Also, different subpopulations of units recorded in the dorsal PAG participate in distinct aspects of defensive behaviors. These findings help us understand the role of the PAG in animal behavior at the single neuron level.

Neural activity of orbitofrontal cortex contributes to control of waiting.

The willingness to wait for delayed reward and information is of fundamental importance for deliberative behaviors. The orbitofrontal cortex (OFC) is thought to be a core component of the neural circuitry underlying the capacity to control waiting. However, the neural correlates of active waiting and the causal role of the OFC in the control of waiting still remain largely unknown. Here, we trained rats to perform a waiting task (waiting for a pseudorandom time to obtain the water reward), and recorded neuronal ensembles in the OFC throughout the task. We observed that subset OFC neurons exhibited ramping activities throughout the waiting process. Receiver operating characteristic analysis showed that neural activities during the waiting period even predicted the trial outcomes (patient vs. impatient) on a trial-by-trial basis. Furthermore, optogenetic activation of the OFC during the waiting period improved the waiting performance, but did not influence rats' movement to obtain the reward. Taken together, these findings reveal that the neural activity in the OFC contributes to the control of waiting.