Inhibitory Gating of Thalamocortical Inputs onto Rat Gustatory Insular Cortex.

In primary gustatory cortex (GC), a subregion of the insular cortex, neurons show anticipatory activity, encode taste identity and palatability, and their activity is related to decision-making. Inactivation of the gustatory thalamus, the parvicellular region of the ventral posteromedial thalamic nucleus (VPMpc), dramatically reduces GC taste responses, consistent with the hypothesis that VPMpc-GC projections carry taste information. Recordings in awake rodents reported that taste-responsive neurons can be found across GC, without segregated spatial mapping, raising the possibility that projections from the taste thalamus may activate GC broadly. In addition, we have shown that cortical inhibition modulates the integration of thalamic and limbic inputs, revealing a potential role for GABA transmission in gating sensory information to GC. Despite this wealth of information at the system level, the synaptic organization of the VPMpc-GC circuit has not been investigated. Here, we used optogenetic activation of VPMpc afferents to GC in acute slice preparations from rats of both sexes to investigate the synaptic properties and organization of VPMpc afferents in GC and their modulation by cortical inhibition. We hypothesized that VPMpc-GC synapses are distributed across GC, but show laminar- and cell-specific properties, conferring computationally flexibility to how taste information is processed. We also found that VPMpc-GC synaptic responses are strongly modulated by the activity regimen of VPMpc afferents, as well as by cortical inhibition activating GABAA and GABAB receptors onto VPMpc terminals. These results provide a novel insight into the complex features of thalamocortical circuits for taste processing.SIGNIFICANCE STATEMENT We report that the input from the primary taste thalamus to the primary gustatory cortex (GC) shows distinct properties compared with primary thalamocortical synapses onto other sensory areas. Ventral posteromedial thalamic nucleus afferents in GC make synapses with excitatory neurons distributed across all cortical layers and display frequency-dependent short-term plasticity to repetitive stimulation; thus, they do not fit the classic distinction between drivers and modulators typical of other sensory thalamocortical circuits. Thalamocortical activation of GC is gated by cortical inhibition, providing local corticothalamic feedback via presynaptic ionotropic and metabotropic GABA receptors. The connectivity and inhibitory control of thalamocortical synapses in GC highlight unique features of the thalamocortical circuit for taste.

LTD at amygdalocortical synapses as a novel mechanism for hedonic learning.

A novel, pleasant taste stimulus becomes aversive if associated with gastric malaise, a form of learning known as conditioned taste aversion (CTA). CTA is common to vertebrates and invertebrates and is an important survival response: eating the wrong food may be deadly. CTA depends on the gustatory portion of the insular cortex (GC) and the basolateral nucleus of the amygdala (BLA) however, its synaptic underpinnings are unknown. Here we report that CTA was associated with decreased expression of immediate early genes in rat GC of both sexes, and with reduced amplitude of BLA-GC synaptic responses, pointing to long-term depression (LTD) as a mechanism for learning. Indeed, association of a novel tastant with induction of LTD at the BLA-GC input in vivo was sufficient to change the hedonic value of a taste stimulus. Our results demonstrate a direct role for amygdalocortical LTD in taste aversion learning.

Versatility and Flexibility of Cortical Circuits.

Cortical circuits are known to be plastic and adaptable, as shown by an impressive body of evidence demonstrating the ability of cortical circuits to adapt to changes in environmental stimuli, development, learning, and insults. In this review, we will discuss some of the features of cortical circuits that are thought to facilitate cortical circuit versatility and flexibility. Throughout life, cortical circuits can be extensively shaped and refined by experience while preserving their overall organization, suggesting that mechanisms are in place to favor change but also to stabilize some aspects of the circuit. First, we will describe the basic organization and some of the common features of cortical circuits. We will then discuss how this underlying cortical structure provides a substrate for the experience- and learning-dependent processes that contribute to cortical flexibility.

Rapid plasticity of visually evoked responses in rat monocular visual cortex.

Sensory cortical circuits are shaped by experience during sensitive periods in development. In the primary visual cortex (V1) altered visual experience results in changes in visual responsiveness of cortical neurons. The experience-dependent refinement of the circuit in V1 is thought to rely on competitive interactions between feedforward circuits driven by the two eyes. However, recent data have provided evidence for an additional role of cortico-cortical circuits in this process. Indeed, experience-dependent changes in intracortical circuits can be induced rapidly and may result in rapid-onset functional changes. Unilateral occlusion of vision rapidly alters visual responsiveness, synaptic strength and connectivity of local circuits in the binocular region of V1 (V1b), where the inputs from the two eyes converge. In the monocular region of rodent V1 (V1m), where feedforward inputs from the ipsilateral eye are virtually absent, visual deprivation induces rapid plasticity in local circuits; however, functional changes seem to occur only after long periods of deprivation. In V1m there is currently no evidence for functional changes occurring within a time window compatible with that of local circuit plasticity. Here, we probed the visual responsiveness of neurons in rat V1m and assessed the effect of one day unilateral eye lid suture on single neuron visual responses. We report a novel form of plasticity within V1m that occurs on a timescale consistent with the earliest known changes in synaptic strength. Our data provide new insights into how sensory experience can rapidly modulate neuronal responses, even in the absence of direct competition between feedforward thalamocortical inputs.

Neurophysiology and Regulation of the Balance Between Excitation and Inhibition in Neocortical Circuits.

Brain function relies on the ability of neural networks to maintain stable levels of activity, while experiences sculpt them. In the neocortex, the balance between activity and stability relies on the coregulation of excitatory and inhibitory inputs onto principal neurons. Shifts of excitation or inhibition result in altered excitability impaired processing of incoming information. In many neurodevelopmental and neuropsychiatric disorders, the excitability of local circuits is altered, suggesting that their pathophysiology may involve shifts in synaptic excitation, inhibition, or both. Most studies focused on identifying the cellular and molecular mechanisms controlling network excitability to assess whether they may be altered in animal models of disease. The impact of changes in excitation/inhibition balance on local circuit and network computations is not clear. Here we report findings on the integration of excitatory and inhibitory inputs in healthy cortical circuits and discuss how shifts in excitation/inhibition balance may relate to pathological phenotypes.

Laminar- and Target-Specific Amygdalar Inputs in Rat Primary Gustatory Cortex.

The primary gustatory cortex (GC) receives projections from the basolateral nucleus of the amygdala (BLA). Behavioral and electrophysiological studies demonstrated that this projection is involved in encoding the hedonic value of taste and is a source of anticipatory activity in GC. Anatomically, this projection is largest in the agranular portion of GC; however, its synaptic targets and synaptic properties are currently unknown. In vivo electrophysiological recordings report conflicting evidence about BLA afferents either selectively activating excitatory neurons or driving a compound response consistent with the activation of inhibitory circuits. Here we demonstrate that BLA afferents directly activate excitatory neurons and two distinct populations of inhibitory neurons in both superficial and deep layers of rat GC. BLA afferents recruit different proportions of excitatory and inhibitory neurons and show distinct patterns of circuit activation in the superficial and deep layers of GC. These results provide the first circuit-level analysis of BLA inputs to a sensory area. Laminar- and target-specific differences of BLA inputs likely explain the complexity of amygdalocortical interactions during sensory processing. SIGNIFICANCE STATEMENT: Projections from the basolateral nucleus of the amygdala (BLA) to the cortex convey information about the emotional value and the expectation of a sensory stimulus. Although much work has been done to establish the behavioral role of BLA inputs to sensory cortices, very little is known about the circuit organization of BLA projections. Here we provide the first in-depth analysis of connectivity and synaptic properties of the BLA input to the gustatory cortex. We show that BLA afferents activate excitatory and inhibitory circuits in a layer-specific and pattern-specific manner. Our results provide important new information about how neural circuits establishing the hedonic value of sensory stimuli and driving anticipatory behaviors are organized at the synaptic level.

Neural processing of gustatory information in insular circuits.

The insular cortex is the primary cortical site devoted to taste processing. A large body of evidence is available for how insular neurons respond to gustatory stimulation in both anesthetized and behaving animals. Most of the reports describe broadly tuned neurons that are involved in processing the chemosensory, physiological and psychological aspects of gustatory experience. However little is known about how these neural responses map onto insular circuits. Particularly mysterious is the functional role of the three subdivisions of the insular cortex: the granular, the dysgranular and the agranular insular cortices. In this article we review data on the organization of the local and long-distance circuits in the three subdivisions. The functional significance of these results is discussed in light of the latest electrophysiological data. A view of the insular cortex as a functionally integrated system devoted to processing gustatory, multimodal, cognitive and affective information is proposed.

Drug-related problems in patients undergoing elective total joint arthroplasty of the hip or knee.

BACKGROUND: Few studies have evaluated drug-related problems in patients undergoing elective total hip or knee arthroplasty. OBJECTIVE: To quantify, for patients undergoing elective total joint arthroplasty, drug-related problems arising from medication orders written before or immediately after the surgery. The primary outcome was the proportion of patients with at least one drug-related problem. The secondary outcomes were the total number and descriptions of these problems, according to the patient's age and the category, type, and severity of the drug-related problem. METHODS: From among patients who underwent elective total joint arthroplasty in a large Canadian regional health authority in 2005, 150 were randomly selected for this chart audit. Patients were included if they had been taking more than one medication before surgery. The charts were examined for drug-related problems, which were categorized according to whether the problem involved a prescription for a home medication, an order for a postoperative medication, or a potential indication for drug therapy. The problems were further described by type and potential severity. RESULTS: Of the 146 patients whose charts were available, 116 (79.5%) had at least one drug-related problem, with a mean of 1.88 drug-related problems per patient. Of the 146 patients, 88 (60.3%) had at least one drug-related problem involving a home medication, 34 (23.3%) had problems related to postoperative orders, and 37 (25.3%) had problems related to a potential indication. The mean number of drug-related problems per patient was 2.03 for those 65 years of age or older and 1.56 for those younger than 65 years (p = 0.09); however, more of the older patients experienced at least one drug-related problem related to home medications (67% [67/100] versus 46% [21/46], p = 0.02). The most common types of problems were medication omissions, illegible drug orders, inappropriate dose or frequency, and drug-allergy interactions. Of the 275 drug-related problems identified, 147 (53.5%) were deemed potentially harmful, 78 (28.4%) required monitoring, and 50 (18.2%) were considered not harmful. CONCLUSIONS: In this study, patients who underwent total joint arthroplasty experienced many drug-related problems. Pharmacists may have opportunities to optimize patient care by identifying, resolving, and preventing drug-related problems in this patient population.

Spinal nerve injury activates prostaglandin synthesis in the spinal cord that contributes to early maintenance of tactile allodynia.

To determine if spinal prostaglandins (PG) contribute to tactile allodynia, male, Sprague-Dawley rats were fitted with either intrathecal (i.t.) microdialysis or drug delivery catheters 3 days before tight ligation of the left lumber 5/6 spinal nerves. Paw withdrawal thresholds (PWT) were determined using von Frey filaments. Ligated rats developed tactile allodynia within 24h, as evidenced by a decrease in PWT in the affected hindpaw (<4 g vs. >15 g control). Sham-operated controls were unchanged from baseline (>15 g). Allodynia was also characterized by a significant increase in the evoked release of PGE(2). Thus, brushing the plantar surface of the affected hindpaw with a cotton-tipped applicator, 5 days postligation, increased the [PGE(2)](dialysate) to 199+/-34% of the prestimulus control period. In contrast, brushing had no detectable effect on release before surgery or in sham-operated animals. Basal release (no brushing) was similar before and after surgery (sham-operated and ligated rats). In a separate group of rats and beginning 2 days after ligation, the acute i.t. injection of S(+)-ibuprofen, SC-51322, SC-236, or SC-560 significantly reversed allodynia (maximum effect=69+/-9, 66+/-6, 57+/-4, 20+/-5%, respectively). R(-)-ibuprofen or vehicle were without effect. The results of this study suggest that: (a). spinal PG synthesis and allodynia-like behaviour are triggered by normally innocuous brushing after spinal nerve ligation; (b). pharmacological disruption of this cascade significantly reverses allodynia; (c). COX-2 is the relevant isozyme; and (d). the PG effect is mediated by spinal EP receptors.