An insula-driven network computes decision uncertainty and promotes abstinence in chronic cocaine users

The anterior insular cortex (AIC) and its interconnected brain regions have been associated with both addiction and decision-making under uncertainty. However, the causal interactions in this uncertainty-encoding neurocircuitry and how these neural dynamics impact relapse remain elusive. Here, we used model-based fMRI to measure choice uncertainty in a motor decision task in 61 individuals with cocaine use disorder (CUD) and 25 healthy controls. CUD participants were assessed before discharge from a residential treatment program and followed for up to 24 weeks. We found that choice uncertainty was tracked by the AIC, dorsal anterior cingulate cortex (dACC), and ventral striatum (VS), across participants. Stronger activations in these regions measured pre-discharge predicted longer abstinence after discharge in individuals with CUD. Dynamic causal modelling revealed an AIC-to-dACC directed connectivity modulated by uncertainty in controls, but a dACC-to-AIC connectivity in CUD participants. This reversal was mostly driven by early-relapsers (<30 days). Furthermore, CUD individuals who displayed a stronger AIC-to-dACC excitatory connection during uncertainty encoding remained abstinent for longer periods. These findings reveal a critical role of an AIC-driven, uncertainty-encoding neurocircuitry in protecting against relapse and promoting abstinence.

Synaptic Interactions Between Forelimb-Related Motor Cortex Neurons in Behaving Primates

We investigated the synaptic interactions between neighboring motor cortex cells in monkeys generating isometric ramp-and-hold torques about the wrist. For pairs of cortical cells the response patterns were determined in response-aligned averages and their synaptic interactions were identified by cross-correlation histograms. Cross-correlograms were compiled for 215 cell pairs and 84 (39%) showed significant features. The most frequently found feature (65/84 = 77%) was a central peak, straddling the origin and representing a source of common synaptic input to both cells. One third of these also had superimposed lagged peaks, indicative of a serial excitatory connection. Pure lagged peaks and lagged troughs, indicative of serial excitatory or inhibitory linkages, respectively, both occurred in 5% of the correlograms with features. A central trough appeared in 13% of the correlograms. The magnitude of the synaptic linkage was measured as the normalized area of the correlogram feature. Plotting the strength of synaptic interaction against response similarity during alternating wrist torques revealed a positive relationship for the correlated cell pairs. A linear fit yielded a positive slope: the pairs with excitatory interactions tended to covary more often than countervary. This linear fit had a positive offset, reflecting a tendency for both covarying and countervarying cells to have excitatory common input. Plotting the cortical location of the cell pairs showed that the strongest interactions occurred between cells separated by <400 microns. The correlational linkages between cells of different cortical layers showed a large proportion of common input to cells in layer V.

Comparison of Morphine and Kainic Acid Microinjections Into Identical PAG Sites on the Activity of RVM Neurons

The rostral ventromedial medulla (RVM) modulates nociception through changes in the activity of two classes of neuron, on- andoff-cells. The activity of these neurons is regulated, in part, by input from the periaqueductal gray (PAG). The objective of this study was to determine whether PAG-mediated antinociception is associated with excitation of both on- andoff-cells in the RVM. Microinjection of morphine into the ventrolateral PAG produced antinociception at 50% of the injection sites. This antinociception was associated with continuous activation of RVM off-cells and inhibition of both the spontaneous and reflex-related activity of RVM on-cells. Microinjection of kainic acid into the same injection sites produced antinociception 92% (37/40) of the time. Although kainic acid directly excites PAG output neurons, the changes in on- and off-cell activity associated with microinjection of kainic acid into the ventrolateral PAG were the same as when morphine was injected. That is,on-cells were inhibited and off-cells were activated. These data indicate that the excitatory connection between the PAG and RVM is directed at RVM off-cells specifically. In addition, these data suggest that direct activation of PAG output neurons, as occurs with kainic acid, is much more likely to produce antinociception than disinhibition of output neurons as occurs following morphine administration.

DYNAMICS OF A SINGLE MODEL NEURON

The parametrized dynamics of a standard nonlinear model neuron with self-interaction is discussed. For units with a self-excitatory connection a hysteresis effect is observed, and the underlying mechanism is identified as that of a cusp catastrophe. This is true for discrete as well as for continuous dynamics. For the discrete dynamics of self-inhibiting units there appear period-doubling bifurcations from stationary states to stable period-2 orbits.

Reduction of Ib autogenetic inhibition in motoneurons during contractions of an ankle extensor muscle in the cat

1. Triceps surae and plantaris (Pl) motoneurons were recorded intracellularly in chloralose or pentobarbital sodium (Nembutal)-anesthetized cats during unfused tetanic contractions of gastrocnemius medialis muscle (GM) produced by stimulating either a cut branch of the GM nerve or the muscle directly. 2. In alpha-motoneurons, during a series of GM twitches at 10/s, contraction-induced inhibitory potentials, probably the result of input from Golgi tendon organs (autogenetic inhibition), rapidly subsided before the end of the series. In contrast, excitatory potentials, probably the result of the activation of spindle primary endings during relaxation from contraction, persisted. 3. In gastrocnemius lateralis-soleus (GL-S) and Pl motoneurons lacking an excitatory connection with Ia afferents from GM, the sustained contraction of this muscle also elicited a declining inhibition. Rapid reduction of contraction-induced autogenetic inhibition was also observed in homonymous gamma-motoneurons. During unfused tetanic contractions lasting 0.5-4s, inhibitory potentials quickly subsided, but an abrupt increase in contractile force elicited a new series of decreasing inhibitory potentials. 4. The assumption that the inhibition induced by GM unfused tetanic contractions was due to activation of homonymous Ib afferents was supported by observations of the effects of electrical stimulation of the GM nerve. In Pl motoneurons lacking an excitatory connection with Ia afferents from GM, repetitive trains applied to the GM nerve, at a strength just above threshold for group I fibers, elicited rapidly declining inhibitory potentials similar to those produced by GM contraction. It was verified that during such stimulation, the amplitude of the group I afferent volleys did not decrease. 5. Reduction of contraction-induced Ib inhibition during sustained GM contraction was still present after a low spinalization of the preparation. As GM tendon organ discharges were verified to persist throughout prolonged contractions, the observed decline of autogenetic inhibition is likely to depend on a spinal mechanism, possibly involving presynaptic inhibition of Ib afferents and/or mutual inhibition of Ib-inhibitory interneurons.

Vertical eye movement-related secondary vestibular neurons ascending in medial longitudinal fasciculus in cat. II. Direct connections with extraocular motoneurons

1. The preceding study in the alert cat has shown that many secondary vestibular axons that ascend in the medial longitudinal fasciculus (MLF) increase their firing rate in proportion to downward eye position. In the present study, projection and termination of these downward-position-vestibular (DPV) neurons within extraocular motoneuron pools were studied electrophysiologically by spike-triggered averaging techniques and morphologically be reconstructing their axonal trajectory after intra-axonal injection of horseradish peroxidase (HRP). 2. Extracellular field potentials recorded within the trochlear nucleus and/or the inferior rectus subdivision of the oculomotor nucleus were averaged by the use of spike potentials of single DPV neurons as triggers. All the crossed-DPV axons tested induced negative unitary field potentials in the trochlear nucleus (n = 9) and in the inferior rectus subdivision of the oculomotor nucleus (n = 5), suggesting that they made monosynaptic excitatory connection with motoneurons in these nuclei. The four crossed-DPV axons tested in the two motoneuron pools induced unitary field potentials in both. The majority of crossed-DPV axons terminated in these nuclei were directly activated from the caudal MLF, indicating that they had descending collaterals projecting to the spinal cord as well. The uncrossed-DPV axons did not induce such unitary field potentials either in the trochlear nucleus (n = 4) or in the inferior rectus subdivision (n = 3). 3. All the uncrossed-DPV axons examined (n = 14) induced positive unitary field potentials in the superior rectus subdivision of the oculomotor nucleus, suggesting that they made monosynaptic inhibitory connections with motoneurons innervating the superior rectus muscle. These uncrossed-DPV axons displayed regular firing patterns and were not activated from the caudal MLF. None of the crossed-DPV axons tested (n = 4) induced unitary field potentials in the superior rectus subdivision. 4. Five crossed-DPV axons were injected with HRP. All these axons ascended in the MLF contralateral to their soma, gave off many collaterals to the trochlear nucleus, and projected more rostrally. For three well-stained axons, numerous terminal branches were also found in the rostroventral part of the contralateral oculomotor nucleus, the area corresponding to the inferior rectus subdivision. Some collaterals in the oculomotor nucleus recrossed the midline to terminate in the medial part of the ipsilateral oculomotor nucleus. Other terminations were observed in the interstitial nucleus of Cajal and in the periaqueductal gray adjacent to the oculomotor nucleus. The crossed axons injected included both regular and irregular types, and three of the four examined were activated from the caudal MLF.(ABSTRACT TRUNCATED AT 400 WORDS)

IDENTIFICATION OF DIRECTIONALLY SELECTIVE MOTION-DETECTING NEURONES IN THE LOCUST LOBULA AND THEIR SYNAPTIC CONNECTIONS WITH AN IDENTIFIED DESCENDING NEURONE

The anatomy and physiology of two directionally selective motion-detecting neurones in the locust are described. Both neurones had dendrites in the lobula, and projected to the ipsilateral protocerebrum. Their cell bodies were located on the posterio-dorsal junction of the optic lobe with the protocerebrum. The neurones were sensitive to horizontal motion of a visual stimulus. One neurone, LDSMD(F), had a preferred direction forwards over the ipsilateral eye, and a null direction backwards. The other neurone, LDSMD(B), had a preferred direction backwards over the ipsilateral eye 1. Motion in the preferred direction caused EPSPs and spikes in the LDSMD neurones. Motion in the null direction resulted in IPSPs 2. Both excitatory and inhibitory inputs were derived from the ipsilateral eye 3. The DSMD neurones responded to velocities of movement up to and beyond 270°s−1 4. The response of both LDSMD neurones showed no evidence of adaptation during maintained apparent or real movement 5. There was a delay of 60–80 ms between a single step of apparent movement, either the preferred or the null direction, and the start of the response 6. There was a monosynaptic, excitatory connection between the LDSMD(B) neurone and the protocerebral, descending DSMD neurone (PDDSMD) identified in the preceding paper (Rind, 1990). At resting membrane potential, a single presynaptic spike did not give rise to a spike in the postsynaptic neurone