Midline Nuclei Research Articles

Parallel pathways of seizure generalization.

Generalized convulsive status epilepticus is a life-threatening emergency, because recurrent convulsions can cause death or injury. A common form of generalized convulsive status epilepticus is of focal onset. The neuronal circuits activated during seizure spread from the hippocampus, a frequent site of seizure origin, to the bilateral motor cortex, which mediates convulsive seizures, have not been delineated. Status epilepticus was initiated by electrical stimulation of the hippocampus. Neurons transiently activated during seizures were labelled with tdTomato and then imaged following brain slice clearing. Hippocampus was active throughout the episode of status epilepticus. Neuronal activation was observed in hippocampus parahippocampal structures: subiculum, entorhinal cortex and perirhinal cortex, septum, and olfactory system in the initial phase status epilepticus. The tdTomato-labelled neurons occupied larger volumes of the brain as seizures progressed and at the peak of status epilepticus, motor and somatosensory cortex, retrosplenial cortex, and insular cortex also contained tdTomato-labelled neurons. In addition, motor thalamic nuclei such as anterior and ventromedial, midline, reticular, and posterior thalamic nuclei were also activated. Furthermore, circuits proposed to be crucial for systems consolidation of memory: entorhinal cortex, retrosplenial cortex, cingulate gyrus, midline thalamic nuclei and prefrontal cortex were intensely active during periods of generalized tonic-clonic seizures. As the episode of status epilepticus waned, smaller volume of brain was activated. These studies suggested that seizure spread could have occurred via canonical thalamocortical pathway and many cortical structures involved in memory consolidation. These studies may help explain retrograde amnesia following seizures.

Central thalamic inactivation impairs the expression of action- and outcome-related responses of medial prefrontal cortex neurons in the rat.

The mediodorsal (MD) and adjacent intralaminar (IL) and midline nuclei provide the main thalamic input to the medial prefrontal cortex (mPFC) and are critical for associative learning and decision-making. MD neurons exhibit activity related to actions and outcomes that mirror responses of mPFC neurons in rats during dynamic delayed non-match to position (dDNMTP), a variation of DNMTP where start location is varied randomly within an open octagonal arena to avoid confounding behavioral events with spatial location. To test whether the thalamus affects the expression of these responses in mPFC, we inhibited the central thalamus unilaterally by microinjecting muscimol at doses and sites found to affect decision-making when applied bilaterally. Unilateral inactivation reduced normalized task-related responses in the ipsilateral mPFC without disrupting behavior needed to characterize event-related neuronal activity. Our results extend earlier findings that focused on delay-related activity by showing that central thalamic inactivation interferes with responses related to actions and outcomes that occur outside the period of memory delay. These findings are consistent with the broad effects of central thalamic lesions on behavioral measures of reinforcement-guided responding. Most (7/8) of the prefrontal response types affected by thalamic inactivation have also been observed in MD during dDNMTP. These results support the hypothesis that MD and IL act as transthalamic gates: monitoring prefrontal activity through corticothalamic inputs; integrating this information with signals from motivational and sensorimotor systems that converge in thalamus; and acting through thalamocortical projections to enhance expression of neuronal responses in the PFC that support adaptive goal-directed behavior.

Efferents of anterior cingulate areas 24a and 24b and midcingulate areas 24a' and 24b' in the mouse.

The anterior cingulate cortex (ACC), constituted by areas 25, 32, 24a and 24b in rodents, plays a major role in cognition, emotion and pain. In a previous study, we described the afferents of areas 24a and 24b and those of areas 24a' and 24b' of midcingulate cortex (MCC) in mice and highlighted some density differences among cingulate inputs (Fillinger et al., Brain Struct Funct 222:1509-1532, 2017). To complete this connectome, we analyzed here the efferents of ACC and MCC by injecting anterograde tracers in areas 24a/24b of ACC and 24a'/24b' of MCC. Our results reveal a common projections pattern from both ACC and MCC, targeting the cortical mantle (intracingulate, retrosplenial and parietal associative cortex), the non-cortical basal forebrain, (dorsal striatum, septum, claustrum, basolateral amygdala), the hypothalamus (anterior, lateral, posterior), the thalamus (anterior, laterodorsal, ventral, mediodorsal, midline and intralaminar nuclei), the brainstem (periaqueductal gray, superior colliculus, pontomesencephalic reticular formation, pontine nuclei, tegmental nuclei) and the spinal cord. In addition to an overall denser ACC projection pattern compared to MCC, our analysis revealed clear differences in the density and topography of efferents between ACC and MCC, as well as between dorsal (24b/24b') and ventral (24a/24a') areas, suggesting a common functionality of these two cingulate regions supplemented by specific roles of each area. These results provide a detailed analysis of the efferents of the mouse areas 24a/24b and 24a'/24b' and achieve the description of the cingulate connectome, which bring the anatomical basis necessary to address the roles of ACC and MCC in mice.

Lesions of the paraventricular thalamic nucleus attenuates prepulse inhibition of the acoustic startle reflex

The paraventricular thalamic nucleus (PVT) is a midline nucleus with strong connections to cortical and subcortical brain regions such as the prefrontal cortex, amygdala, nucleus accumbens and hippocampus and receives strong projections from brain stem nuclei. Prepulse inhibition (PPI) is mediated and modulated by complex cortical and subcortical networks that are yet to be fully identified in detail. Here, we suggest that the PVT may be an important brain region for the modulation of PPI. In our study, the paraventricular thalamic nuclei of rats were electrolytically lesioned. Two weeks after the surgery, the PPI responses of the animals were monitored and recorded using measurements of acoustic startle reflex. Our results show that disruption of the PVT dramatically attenuated PPI at prepulse intensities of 74, 78 and 86dB compared to that in the sham lesion group. Thus, we suggest that the PVT may be an important part of the PPI network in the rat brain.

Interactions of Hallucinogens with the Glutamatergic System: Permissive Network Effects Mediated Through Cortical Layer V Pyramidal Neurons.

Recordings made from layer V (L5) pyramidal cells of the prefrontal cortex (PFC) and neocortex in rodent slice preparations have shown that serotonin (5-hydroxytryptamine, 5-HT) and serotonergic hallucinogens induce an increase in the frequency of spontaneous excitatory postsynaptic currents (EPSCs) in the apical dendritic field by activating 5-HT2A receptors. Serotonergic hallucinogens induce late EPSCs and increase recurrent network activity when subcortical or mid-cortical regions are stimulated at low frequencies (e.g., 0.1Hz). A range of agonists or positive allosteric modulators (PAMs) for mostly Gi/o-coupled receptors, including metabotropic glutamate2 (mGlu2), adenosine A1, or μ-opioid receptors, suppress these effects of 5-HT2A receptor stimulation. Furthermore, a range of mostly Gq/11-coupled receptors (including orexin2 [OX2]; α1-adrenergic, and mGlu5 receptors) similarly induce glutamate (Glu) release onto L5 pyramidal cells. Evidence implicates a number of brain regions in mediating these effects of serotonergic hallucinogens and Gq/11-coupled receptors including the midline and intralaminar thalamic nuclei, claustrum, and neurons in deep PFC. These effects on 5-HT2A receptors and related GPCRs appear to play a major role in the behavioral effects of serotonergic hallucinogens, such as head twitches in rodents and higher order behaviors such as rodent lever pressing on the differential-reinforcement-of-low rate 72-s (DRL 72-s) schedule. This implies that the effects of 5-HT2A receptor activation on the activity of L5 pyramidal cells may be responsible for mediating a range of behaviors linked to limbic circuitry with connectivity between the PFC, striatum, thalamus, claustrum, striatum, amygdala, and the hippocampal formation.

Cocaine Experience Enhances Thalamo-Accumbens N-Methyl-D-Aspartate Receptor Function

BackgroundExcitatory synaptic transmission in the nucleus accumbens (NAc) is a key biological substrate underlying behavioral responses to psychostimulants and susceptibility to relapse. Studies have demonstrated that cocaine induces changes in glutamatergic signaling at distinct inputs to the NAc. However, consequences of cocaine experience on synaptic transmission from the midline nuclei of the thalamus (mThal) to the NAc have yet to be reported. MethodsTo examine synapses from specific NAc core inputs, we recorded light-evoked excitatory postsynaptic currents following viral-mediated expression of channelrhodopsin-2 in the mThal, prefrontal cortex (PFC), or basolateral amygdala from acute brain slices. To identify NAc medium spiny neuron subtypes, we used mice expressing tdTomato driven by the promoter for dopamine receptor subtype 1 (D1). We recorded N-methyl-D-aspartate receptor (NMDAR) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) properties to evaluate synaptic adaptations induced by cocaine experience, a 5-day cocaine exposure followed by 2 weeks of abstinence. ResultsExcitatory inputs to the NAc core displayed differential NMDAR properties, and cocaine experience uniquely altered AMPAR and NMDAR properties at mThal-D1(+), mThal-D1(−), and PFC-D1(+) synapses, but not at PFC-D1(−) synapses. Finally, at mThal-D1(+) synapses, cocaine enhanced GluN2C/D function and NMDAR-dependent synaptic plasticity. ConclusionsOur results identify contrasting cocaine-induced AMPAR and NMDAR modifications at mThal-NAc and PFC-NAc core synapses. These changes include an enhancement of NMDAR function and plasticity at mThal-D1(+) synapses. Incorporation of GluN2C/D-containing NMDARs most likely underlies these phenomena and represents a potential therapeutic target for psychostimulant use disorders.

Inflammatory cytokines influence measures of white matter integrity in bipolar disorder

Midcingulate cortex (MCC) has risen in prominence as human imaging identifies unique structural and functional activity therein and this is the first review of its structure, connections, functions and disease vulnerabilities. The MCC has two divisions (anterior, aMCC and posterior, pMCC) that represent functional units and the cytoarchitecture, connections and neurocytology of each is shown with immunohistochemistry and receptor binding. The MCC is not a division of anterior cingulate cortex (ACC) and the “dorsal ACC” designation is a misnomer as it incorrectly implies that MCC is a division of ACC. Interpretation of findings among species and developing models of human diseases requires detailed comparative studies which is shown here for five species with flat maps and immunohistochemistry (human, monkey, rabbit, rat, mouse). The largest neurons in human cingulate cortex are in layer Vb of area 24 d in pMCC which project to the spinal cord. This area is part of the caudal cingulate premotor area which is involved in multisensory orientation of the head and body in space and neuron responses are tuned for the force and direction of movement. In contrast, the rostral cingulate premotor area in aMCC is involved in action-reinforcement associations and selection based on the amount of reward or aversive properties of a potential movement. The aMCC is activated by nociceptive information from the midline, mediodorsal and intralaminar thalamic nuclei which evoke fear and mediates nocifensive behaviors. This subregion also has high dopaminergic afferents and high dopamine-1 receptor binding and is engaged in reward processes. Opposing pain/avoidance and reward/approach functions are selected by assessment of potential outcomes and error detection according to feedback-mediated, decision making. Parietal afferents differentially terminate in MCC and provide for multisensory control in an eye- and head-centric manner. Finally, MCC vulnerability in human disease confirms the unique organization of MCC and supports the predictive validity of the MCC dichotomy. Vulnerability of aMCC is shown in chronic pain, obsessive-compulsive disorder with checking symptoms and attention-deficit/hyperactivity disorder and methylphenidate and pain medications selectively impact aMCC. In contrast, pMCC vulnerabilities are for progressive supranuclear palsy, unipolar depression and posttraumatic stress disorder. Thus, there is an emerging picture of the organization, functions and diseases of MCC. Future work will take this type of modular analysis to individual areas of which there are at least 10 in MCC.

A deficit in familiarity-driven recognition in a right-sided mediodorsal thalamic lesion patient.

According to a still-controversial view of recognition, projections between the perirhinal cortex and the medial subdivision of the mediodorsal thalamic nucleus (mMDT) support the mnemonic processes underlying familiarity, whereas a separate extended hippocampal system is critical for the recollection of episodic details during recognition. In this study, we examined item recognition, familiarity, and recollection for faces and words in a patient (OG) with a right-sided lesion centered on the mMDT, which encroached on the central medial midline nucleus and may have resulted in partial disconnection of the mammillothalamic tract. On the basis of OG's neuropathology, the dual-process signal-detection (DPSD) high-threshold theory and the material-specific hypothesis of long-term memory together predicted a material-specific impairment in familiarity for novel facial memoranda, with a lesser decline in recollection of novel faces at short retention intervals. No abnormalities in either familiarity- or recollection-driven recognition of verbal memoranda were expected. Comparing the performance of OG and that of a group of 10 age-, sex-, and IQ-matched healthy controls, the remember-know procedure revealed the dissociations predicted by the material-specific and DPSD hypotheses: With recognition of previously novel faces, OG showed a deficit in familiarity-driven recognition that was significantly greater than the insignificant reduction in his recollection. All components of his word recognition were, however, preserved. A memory profile, marked by a dissociation between familiarity and recollection, fits naturally with the DPSD model and is incompatible with the idea that these kinds of memories reflect different degrees of trace strength.

Quantitative Analyses of the Projection of Individual Neurons from the Midline Thalamic Nuclei to the Striosome and Matrix Compartments of the Rat Striatum.

A fundamental organizing principle of the striatum is the striosome/matrix system that is defined by inputs/outputs and neurochemical markers. The thalamostriatal projection is highly heterogeneous originating in many subnuclei of the thalamus including the midline (ML) and intralaminar (IL) nuclei. We examined the dendritic morphology and axonal trajectory of 15 ML and 11 IL neurons by single-neuron labeling with viral vectors in combination with mu-opioid receptor immunostaining in rat brains. Dendritic and axonal morphology defined ML neurons as type II cells consisting of at least two subclasses according to the presence or absence of striatal axon collaterals. In the striatum, ML neurons preferentially innervated striosomes, whereas parafascicular neurons preferentially innervated the matrix. Almost all single thalamostriatal neurons favoring striosome or matrix compartments also innervated the cerebral cortical areas that supplied cortical input to the same striatal compartment. We thus revealed that thalamostriatal projections are highly organized 1) by the similarity in morphological characteristics and 2) their preference for the striatal compartments and cortical areas. These findings demonstrate that the functional properties of striatal compartments are influenced by both their cortical and thalamic afferents presumably with a different time latency and support selective dynamics for the striosome and matrix compartments.

Hypnosis and pain perception: An Activation Likelihood Estimation (ALE) meta-analysis of functional neuroimaging studies

Background and objectiveSeveral studies reported that hypnosis can modulate pain perception and tolerance by affecting cortical and subcortical activity in brain regions involved in these processes. We conducted an Activation Likelihood Estimation (ALE) meta-analysis on functional neuroimaging studies of pain perception under hypnosis to identify brain activation–deactivation patterns occurring during hypnotic suggestions aiming at pain reduction, including hypnotic analgesic, pleasant, or depersonalization suggestions (HASs). Databases and data treatmentWe searched the PubMed, Embase and PsycInfo databases; we included papers published in peer-reviewed journals dealing with functional neuroimaging and hypnosis-modulated pain perception. The ALE meta-analysis encompassed data from 75 healthy volunteers reported in 8 functional neuroimaging studies. ResultsHASs during experimentally-induced pain compared to control conditions correlated with significant activations of the right anterior cingulate cortex (Brodmann’s Area [BA] 32), left superior frontal gyrus (BA 6), and right insula, and deactivation of right midline nuclei of the thalamus. ConclusionsHASs during experimental pain impact both cortical and subcortical brain activity. The anterior cingulate, left superior frontal, and right insular cortices activation increases could induce a thalamic deactivation (top-down inhibition), which may correlate with reductions in pain intensity.

The frequency of spontaneous seizures in rats correlates with alterations in sensorimotor gating, spatial working memory, and parvalbumin expression throughout limbic regions

Cognitive deficits and psychotic symptoms are highly prevalent in patients with temporal lobe epilepsy (TLE). Imaging studies in humans have suggested that these comorbidities are associated with atrophy in temporal lobe structures and other limbic regions. It remains to be clarified whether TLE comorbidities are due to the frequency of spontaneous seizures or to limbic structural damage per se. Here, we used the pilocarpine model of chronic spontaneous seizures to evaluate the possible association of seizure frequency with sensorimotor gating, spatial working memory, and neuropathology throughout limbic regions. For TLE modeling, we induced a 2-h status epilepticus by the systemic administration of lithium–pilocarpine. Once spontaneous seizures were established, we tested the locomotor activity (open field), spatial working memory (eight-arm radial maze), and sensorimotor gating (prepulse inhibition of acoustic startle). After behavioral testing, the brains were sectioned for hematoxylin–eosin staining (cell density) and parvalbumin immunohistochemistry (GABAergic neuropil) in the prefrontal cortex, nucleus accumbens, thalamus, amygdala, hippocampus, and entorhinal cortex. The animal groups analyzed included chronic epileptic rats, their controls, and rats that received lithium–pilocarpine but eventually failed to express status epilepticus or spontaneous seizures. Epileptic rats showed deficits in sensorimotor gating that negatively correlated with the radial maze performance, and impairments in both behavioral tests correlated with seizure frequency. In addition to neuronal loss at several sites, we found increased parvalbumin immunostaining in the prefrontal cortex (infralimbic area), thalamus (midline and reticular nuclei), amygdala, Ammon’s horn, dentate gyrus, and entorhinal cortex. These tissue changes correlated with seizure frequency and impairments in sensorimotor gating. Our work indicates that chronic seizures might impact the inhibitory–excitatory balance in the temporal lobe and its interconnected limbic regions, which could increase the likelihood of cognitive deficits and interictal psychiatric disorders.

Evidence for spatially-responsive neurons in the rostral thalamus.

Damage involving the anterior thalamic and adjacent rostral thalamic nuclei may result in a severe anterograde amnesia, similar to the amnesia resulting from damage to the hippocampal formation. Little is known, however, about the information represented in these nuclei. To redress this deficit, we recorded units in three rostral thalamic nuclei in freely-moving rats [the parataenial nucleus (PT), the anteromedial nucleus (AM) and nucleus reuniens NRe]. We found units in these nuclei possessing previously unsuspected spatial properties. The various cell types show clear similarities to place cells, head direction cells, and perimeter/border cells described in hippocampal and parahippocampal regions. Based on their connectivity, it had been predicted that the anterior thalamic nuclei process information with high spatial and temporal resolution while the midline nuclei have more diffuse roles in attention and arousal. Our current findings strongly support the first prediction but directly challenge or substantially moderate the second prediction. The rostral thalamic spatial cells described here may reflect direct hippocampal/parahippocampal inputs, a striking finding of itself, given the relative lack of place cells in other sites receiving direct hippocampal formation inputs. Alternatively, they may provide elemental thalamic spatial inputs to assist hippocampal spatial computations. Finally, they could represent a parallel spatial system in the brain.

Transient relay function of midline thalamic nuclei during long-term memory consolidation in humans.

To test the hypothesis that thalamic midline nuclei play a transient role in memory consolidation, we reanalyzed a prospective functional MRI study, contrasting recent and progressively more remote memory retrieval. We revealed a transient thalamic connectivity increase with the hippocampus, the medial prefrontal cortex (mPFC), and a parahippocampal area, which decreased with time. In turn, mPFC-parahippocampal connectivity increased progressively. These findings support a model in which thalamic midline nuclei serve as a hub linking hippocampus, mPFC, and posterior representational areas during memory retrieval at an early (2 h) stage of consolidation, extending classical systems consolidation models by attributing a transient role to midline thalamic nuclei.

Immunohistochemical mapping of neurotensin in the alpaca diencephalon.

The distribution of the immunoreactive cell bodies and fibers containing neurotensin in the alpaca diencephalon was determined by an immunohistochemical technique. The study was carried out in four male alpacas that lived at sea level. Brains of deeply anesthetized animals were fixed by perfusion with 4% paraformaldehyde. Cryostat sections were stained by a standard immunohistochemical method. Cell bodies containing neurotensin were observed in the zona incerta and hypothalamus. A low/moderate density of these cell bodies was observed in the lateral hypothalamic area, anterior and dorsal hypothalamic areas, suprachiasmatic nucleus, periventricular region of the hypothalamus and in the ventromedial hypothalamic nucleus. In both thalamus and hypothalamus, immunoreactive fibers showed a widespread distribution. In the thalamus, a high density of these fibers was mainly found in the midline nuclei, whereas in the hypothalamus a high density was in general observed in the whole structure. In comparison with other mammals, the thalamus of the alpaca showed the most widespread distribution of neurotensin-immunoreactive fibers. The widespread distribution of neurotensin through the alpaca diencephalon suggests that the peptide can be involved in many physiological actions.

Evolution of mammalian sensorimotor cortex: thalamic projections to parietal cortical areas in Monodelphis domestica.

The current experiments build upon previous studies designed to reveal the network of parietal cortical areas present in the common mammalian ancestor. Understanding this ancestral network is essential for highlighting the basic somatosensory circuitry present in all mammals, and how this basic plan was modified to generate species specific behaviors. Our animal model, the short-tailed opossum (Monodelphis domestica), is a South American marsupial that has been proposed to have a similar ecological niche and morphology to the earliest common mammalian ancestor. In this investigation, we injected retrograde neuroanatomical tracers into the face and body representations of primary somatosensory cortex (S1), the rostral and caudal somatosensory fields (SR and SC), as well as a multimodal region (MM). Projections from different architectonically defined thalamic nuclei were then quantified. Our results provide further evidence to support the hypothesized basic mammalian plan of thalamic projections to S1, with the lateral and medial ventral posterior thalamic nuclei (VPl and VPm) projecting to S1 body and S1 face, respectively. Additional strong projections are from the medial division of posterior nucleus (Pom). SR receives projections from several midline nuclei, including the medial dorsal, ventral medial nucleus, and Pom. SC and MM show similar patterns of connectivity, with projections from the ventral anterior and ventral lateral nuclei, VPm and VPl, and the entire posterior nucleus (medial and lateral). Notably, MM is distinguished from SC by relatively dense projections from the dorsal division of the lateral geniculate nucleus and pulvinar. We discuss the finding that S1 of the short-tailed opossum has a similar pattern of projections as other marsupials and mammals, but also some distinct projections not present in other mammals. Further we provide additional support for a primitive posterior parietal cortex which receives input from multiple modalities.

Connections of the macaque Granular Frontal Opercular (GrFO) area: a possible neural substrate for the contribution of limbic inputs for controlling hand and face/mouth actions.

We traced the connections of the macaque Granular Frontal Opercular (GrFO) area, located in the rostralmost part of the frontal opercular margin, and compared them with those of the caudally adjacent dorsal opercular (DO) and precentral opercular (PrCO) areas. Area GrFO displays strong connections with areas DO, PrCO, and ventrolateral prefrontal (VLPF) area 12l, and even more with the mostly hand-related ventral premotor (PMv) area F5a. Other connections involve the mostly face/mouth-related PMv area F5c, the arm-related area F6/pre-SMA, the hand-related fields of VLPF areas 46v and 12r, and area SII, mostly the hand representation. Furthermore, area GrFO shows rich connectivity with several components of the limbic system including orbitofrontal areas 12o, 12m, and 11, the agranular and dysgranular insula, the agranular cingulate area 24, and the amygdala. Thalamic afferents originate primarily from the parvocellular and the magnocellular subdivisions of the mediodorsal nucleus and from midline and intralaminar nuclei. This connectivity pattern clearly distinguishes area GrFO from areas DO and PrCO, characterized by a connectivity mostly involving oral sensorimotor and gustatory areas/subcortical structures. The present data suggest, based on connectivity patterns, an involvement of area GrFO in the cortical circuits for controlling goal-directed hand and face/mouth actions. In this context, area GrFO could represent a gateway for the access of limbic inputs, for example about subjective values, emotional significance of stimuli or internal states, to the PMv areas involved in selecting appropriate goal-directed hand and mouth/face actions.

Serotonergic fibers distribution in the midline and intralaminar thalamic nuclei in the rock cavy (Kerodon rupestris)

The thalamic midline/intralaminar complex is part of the higher-order thalamus, which receives little sensory input, and instead forms extensive cortico-thalamo-cortical pathways. The midline thalamic nuclei connect with the medial prefrontal cortex and the medial temporal lobe. On the other hand, the intralaminar nuclei connect with the fronto-parietal cortex. Taking into account this connectivity pattern, it is not surprising that the midline/intralaminar complex has been implicated in a broad variety of cognitive functions, including memory process, attention and orientation, and also reward-based behavior. Serotonin (5-HT) is a neurotransmitter that exerts different post-synaptic roles. Serotonergic neurons are almost entirely restricted to the raphe nuclei and the 5-HT fibers are distributed widely throughout the brain, including the midline/intralaminar complex. The present study comprises a detailed description of the morphologic features and semiquantitative analysis of 5-HT fibers distribution in the midline/intralaminar complex in the rock cavy, a typical rodent of the Northeast region of Brazil, which has been used by our group as an anatomical model to expand the comprehension about phylogeny on the nervous system. The 5-HT fibers in the midline/intralaminar nuclei of the rock cavy were classified into three distinct categories: (1) beaded fibers, which are relatively fine and endowed with large varicosities; (2) fine fibers, with thin axons and small varicosities uniformly distributed in whole axon; and (3) stem axons, showing thick non-varicose axons. Moreover, the density of 5-HT fibers is variable among the analyzed nuclei. On the basis of this diversity of the morphological fibers and the differential profile of optical density among the midline/intralaminar nuclei of the rock cavy, we conclude that the serotonergic system uses a diverse morphologic apparatus to exert a large functional repertory in the midline/intralaminar thalamic nuclei.

Novel coupling between TRPC-like and KNa channels modulates low threshold spike-induced afterpotentials in rat thalamic midline neurons

Neurons in thalamic midline and paraventricular nuclei (PVT) display a unique slow afterhyperpolarizing potential (sAHP) following the low threshold spike (LTS) generated by activation of their low voltage Ca2+ channels. We evaluated the conductances underlying this sAHP using whole-cell patch-clamp recordings in rat brain slice preparations. Initial observations recorded in the presence of TTX revealed a marked dependency of the LTS-induced sAHP on extracellular Na+: replacing Na+ with TRIS+ in the external medium eliminated the LTS-induced sAHP; substitution of Na+ with either Li+ or choline+ in the external medium resulted in a gradual loss of the sAHP and its replacement with a prolonged slow afterdepolarizing potential (sADP). The LTS-induced sAHP was reduced by quinidine and potentiated by loxapine, suggesting involvement of KNa-like channels. Canonical transient receptor potential (TRPC) channels were considered the source for Na+ based on observations that the sAHP was suppressed by nonselective TRPC channel blockers (2-APB, flufenamic acid and ML204) but unchanged in the presence of TRPV1 channel blocker (SB-366791). In addition, after replacement of Na+ with Li+, the isolated LTS-induced sADP was significantly suppressed in the presence of 2-APB or ML204, after replacement of extracellular Ca2+ with Sr2+, and by intracellular Ca2+ chelation with EGTA, data that collectively suggest involvement of Ca2+-activated TRPC-like conductances containing TRPC4/5 subunits. The isolated LTS-induced sADP also exhibited a strong voltage dependency, decreasing at hyperpolarizing potentials, further support for involvement of TRPC4/5 subunits. This sADP exhibited neurotransmitter receptor sensitivity, with suppression by 5-CT, a 5-HT7 receptor agonist, and enhancement by the neuropeptide orexin A. These data suggest that LTS-induced slow afterpotentials reflect a simultaneous interplay between KNa and TRPC-like conductances, novel for midline thalamic neurons.

Thalamic neuromodulation and its implications for executive networks.

The thalamus is a key structure that controls the routing of information in the brain. Understanding modulation at the thalamic level is critical to understanding the flow of information to brain regions involved in cognitive functions, such as the neocortex, the hippocampus, and the basal ganglia. Modulators contribute the majority of synapses that thalamic cells receive, and the highest fraction of modulator synapses is found in thalamic nuclei interconnected with higher order cortical regions. In addition, disruption of modulators often translates into disabling disorders of executive behavior. However, modulation in thalamic nuclei such as the midline and intralaminar groups, which are interconnected with forebrain executive regions, has received little attention compared to sensory nuclei. Thalamic modulators are heterogeneous in regards to their origin, the neurotransmitter they use, and the effect on thalamic cells. Modulators also share some features, such as having small terminal boutons and activating metabotropic receptors on the cells they contact. I will review anatomical and physiological data on thalamic modulators with these goals: first, determine to what extent the evidence supports similar modulator functions across thalamic nuclei; and second, discuss the current evidence on modulation in the midline and intralaminar nuclei in relation to their role in executive function.

A role for midline and intralaminar thalamus in the associative blocking of Pavlovian fear conditioning.

Fear learning occurs in response to positive prediction error, when the expected outcome of a conditioning trial exceeds that predicted by the conditioned stimuli present. This role for error in Pavlovian association formation is best exemplified by the phenomenon of associative blocking, whereby prior fear conditioning of conditioned stimulus (CS) A is able to prevent learning to CSB when they are conditioned in compound. The midline and intralaminar thalamic nuclei (MIT) are well-placed to contribute to fear prediction error because they receive extensive projections from the midbrain periaqueductal gray—which has a key role in fear prediction error—and project extensively to prefrontal cortex and amygdala. Here we used an associative blocking design to study the role of MIT in fear learning. In Stage I rats were trained to fear CSA via pairings with shock. In Stage II rats received compound fear conditioning of CSAB paired with shock. On test, rats that received Stage I training expressed less fear to CSB relative to control rats that did not receive this training. Microinjection of bupivacaine into MIT prior to Stage II training had no effect on the expression of fear during Stage II and had no effect on fear learning in controls, but prevented associative blocking and so enabled fear learning to CSB. These results show an important role for MIT in predictive fear learning and are discussed with reference to previous findings implicating the midline and posterior intralaminar thalamus in fear learning and fear responding.