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

Impact of the pulvinar on the ventral pathway of the cat visual cortex

Signals from the retina are relayed to the lateral geniculate nucleus from which they are sent to the primary visual cortex. At the cortical level, the information is transferred across several visual areas in which the complexity of the processing increases progressively. Anatomical and functional evidence demonstrate the existence of two main pathways in visual cortex processing distinct features of the visual information: the dorsal and ventral streams. Cortical areas composing the dorsal stream are implicated mostly in motion processing while those comprising the ventral stream are involved in the processing of form and colour. This classic view of the cortical functional organization is challenged by the existence of reciprocal connections of visual cortical areas with the thalamic nucleus named pulvinar. These connections allow the creation of a trans-thalamic pathway that parallels the cortico-cortical communications across the visual hierarchy. The main goal of the present thesis is twofold: first, to obtain a better comprehension of the processing of light increments and decrements in an area of the cat ventral stream (area 21a); second, to characterize the nature of the thalamo-cortical inputs from the cat lateral posterior nucleus (LP) to area 21a. In study #1, we investigated the spatiotemporal response profile of neurons from area 21a to light increments (brights) and decrements (darks) using a reverse correlation analysis of a sparse noise stimulus. Our findings showed that 21a neurons exhibited stronger responses to darks with receptive fields exhibiting larger dark subfields. However, no differences were found between the temporal dynamics of brights and darks. In comparison with the primary visual cortex, the dark preference in area 21a was found to be strongly enhanced, supporting the notion that the asymmetries between brights and darks are transmitted and amplified along the ventral stream. In study #2, we investigated the impact of the reversible pharmacological inactivation of the LP nucleus on the contrast response function (CRF) of neurons from area 21a and the primary visual cortex (area 17). The thalamic inactivation yielded distinct effects on both cortical areas. While in area 17 the LP inactivation caused a slight decrease in the response gain, in area 21a a strong increase was observed. Thus, our findings suggest that the LP exerts a modulatory influence on the cortical processing along the ventral stream with stronger impact on higher order extrastriate areas. Taken together, our findings allowed a better comprehension of the functional properties of the cat ventral stream and contributed to the current knowledge on the role of the pulvinar on the cortico-thalamo-cortical processing of visual information.Les signaux provenant de la rétine sont relayés dans le corps géniculé latéral où ils sont envoyés au cortex visuel primaire. L’information passe ensuite à travers plusieurs aires visuelles où la complexité du traitement augmente progressivement. Des données tant anatomiques que fonctionnelles ont démontré l’existence de deux voies principales qui traitent différentes propriétés de l’information visuelle : les voies dorsale et ventrale. Les aires corticales composant la voie dorsale sont impliquées principalement dans le traitement du mouvement tandis que les aires de la voie ventrale sont impliquées dans le traitement de la forme et de la couleur. Cette vision classique de l’organisation fonctionnelle du cortex est toutefois remise en question par l’existence de connections réciproques entre les aires corticales visuelles et le pulvinar, un noyau thalamique. En effet, ces connections permettent la création d’une voie trans-thalamique parallèle aux connections cortico-corticales à travers la hiérarchie visuelle. Le but principal de la présente thèse consiste en deux volets : le premier est d’obtenir une meilleure compréhension du traitement des incréments et décréments de la lumière dans une aire de la voie ventrale du chat (aire 21a); le second est de caractériser la nature des inputs thalamo-corticaux du noyau latéral postérieur (LP) à l’aire 21a chez le chat. Dans l’étude #1, nous avons investigué le profil spatiotemporel des réponses des neurones de l’aire 21a aux incréments (blancs) et décréments (noirs) de lumière en utilisant l’analyse de corrélation inverse d’un stimulus de bruit épars. Les neurones de l’aire 21a ont répondu plus fortement aux stimuli noirs, en montrant des champs récepteurs avec des sous-champs noirs plus larges. Cependant, aucune différence n’a été trouvée en ce qui concerne les dynamiques temporelles des réponses aux blancs et aux noirs. En comparaison avec le cortex visuel primaire, la préférence aux stimuli noirs dans l’aire 21a s’est avérée fortement augmentée. Ces données indiquent que les asymétries entre les réponses aux blancs et aux noirs sont transmises et amplifiées à travers la voie ventrale. Dans l’étude #2, nous avons investigué l’impact de l’inactivation pharmacologique réversible du noyau LP sur la fonction de réponse au contraste (CRF) des neurones de l’aire 21a et du cortex visuel primaire (aire 17). L’inactivation a eu différents effets dans les deux aires corticales. Alors que, dans l’aire 17, l’inactivation du LP a causé une légère réduction du gain de la réponse, une forte augmentation a été observée dans l’aire 21a. Ainsi, nos résultats suggèrent que le LP exerce une influence modulatrice dans le traitement cortical à travers la voie ventrale avec un impact plus important dans des aires extrastriées de plus haut niveau. Nos résultats ont permis d’avoir une meilleure compréhension des propriétés fonctionnelles de la voie ventrale du chat et de contribuer à enrichir les connaissances actuelles sur le rôle du pulvinar dans le traitement cortico-thalamo-cortical de l’information visuelle

The thalamic reticular nucleus: a functional hub for thalamocortical network dysfunction in schizophrenia and a target for drug discovery

The thalamus (comprising many distinct nuclei) plays a key role in facilitating sensory discrimination and cognitive processes through connections with the cortex. Impaired thalamocortical processing has long been considered to be involved in schizophrenia. In this review we focus on the thalamic reticular nucleus (TRN) providing evidence for it being an important communication hub between the thalamus and cortex and how it may play a key role in the pathophysiology of schizophrenia. We first highlight the functional neuroanatomy, neurotransmitter localisation and physiology of the TRN. We then present evidence of the physiological roles of the TRN in relation to oscillatory activity, cognition and behaviour. Next we discuss the role of the TRN in rodent models of risk factors for schizophrenia (genetic and pharmacological) and provide evidence for TRN deficits in schizophrenia. Finally we discuss new drug targets for schizophrenia in relation to restoring TRN circuitry dysfunction

A Paleocortico-Thalamo-Cortical Circuit Operating Giant Synapses

The thalamus is a critical relay station in the pathway for sensory information to the cortex and additionally important for the intercortical information transfer. An exception is the olfactory system, as it does not require a thalamic relay step before the information reaches the cortex. Olfactory receptor neurons send axonal projections to the olfactory bulb, from where the information proceeds to the primary olfactory cortex. It is only from the piriform cortex (PIR) that the information is passed to the prefrontal cortex via direct projections and via the mediodorsal thalamus (MD). Aside the for a sensory system exceptional connectivity, does this circuit also stand out against other cortico-thalamo-cortical loops. The PIR belongs to the paleocortex instead of neocortex, the contributor to most other cortico-thalamo-cortical loops. This situation raises the question if paleocorticothalamic projections have the same function as their subcorticothalamic or neocorticothalamic equivalents? In this thesis, I utilize a highly precise spatiotemporal gene transfer system via adeno-associated viruses to label PIR synapses. In acute slice preparations these synapses may be excited individually by juxtapositioned near field simulation electrodes. Based on the kinetics of the evoked postsynaptic currents and immunohistological stainings, I propose glutamate as the principle neurotransmitter. The PIR-MD synapse displays short-term depression, as it has been shown for other thalamic afferences, classified as “drivers”. In an electronmicroscopic preparation the complex dendritic interface of PIR-MD synapses becomes apparent. Often multiple dendritic excrescences invade the presynaptic profile. The presynaptic lumen is filled with vesicles and mitochondria. Altogether the morphology is that of a typical driver synapse in the thalamus. Surprisingly, I found chemical synapses onto intermediate stretches of labeled axons, a constellation that has not been described in MD or elsewhere previously. In summary, the results show that the olfactory brain circuit may have an additional level of complexity, imposed by axo-axonal contacts, and that PIR-MD synapses function like driver synapses in other transthalamic projections. However, as the term “driver” suggests that it always evokes postsynaptic action potentials, which is not true for the PIR-MD synapse, the recently proposed term “class I” synapse is adopted

Deficient responses from the lateral geniculate nucleus in humans with amblyopia

Amblyopia or lazy eye is the most common cause of uniocular blindness in adults. It is caused by a disruption to normal visual development as a consequence of unmatched inputs from the two eyes in early life, arising from a turned eye (strabismus), unequal refractive error (anisometropia) or form deprivation (e.g. cataract). Animal models based on extracellular recordings in anesthetized animals suggest that the earliest site of the anomaly in the primate visual pathway is the primary visual cortex (corresponding to the striate cortex, cytoarchitectonic area 17 and area V1), which is where inputs from the two eyes are first combined in an excitatory fashion, whereas more distal and monocular processing structures such as the retina and lateral geniculate nucleus (LGN) are normal. Using high-field functional magnetic resonance imaging in a group of human adults with amblyopia, we demonstrate that functional deficits are first observable at a thalamic level, that of the LGN. Our results suggest the need to re-evaluate the current models of amblyopia that are based on the assumption of a purely cortical dysfunction, as well as the role for the LGN in visual development

The thalamus as a putative biomarker in neurodegenerative disorders

Objective: This review provides a brief account of the clinically relevant functional neuroanatomy of the thalamus, before considering the utility of various modalities utilised to image the thalamus and technical challenges therein, and going on to provide an overview of studies utilising structural imaging techniques to map thalamic morphology in the spectrum of neurodegenerative disorders. Methods: A systematic search was conducted for peer-reviewed studies involving structural neuroimaging modalities investigating the morphology (shape and/ or size) of the thalamus in the spectrum of neurodegenerative disorders. Results: Whilst the precise role of the thalamus in the healthy brain remains unclear, there is a large body of knowledge accumulating which defines more precisely its functional connectivity within the connectome, and a burgeoning literature implicating its involvement in neurodegenerative disorders. It is proposed that correlation of clinical features with thalamic morphology (as a component of a quantifiable subcortical connectome) will provide a better understanding of neuropsychiatric dysfunction in various neurodegenerative disorders, potentially yielding clinically useful endophenotypes and disease biomarkers. Conclusions: Thalamic biomarkers in the neurodegenerative disorders have great potential to provide clinically meaningful knowledge regarding not only disease onset and progression, but may yield targets of and perhaps a way of gauging response to future disease-modifying modalities

Cognitive Functions and Neurodevelopmental Disorders Involving the Prefrontal Cortex and Mediodorsal Thalamus

The mediodorsal nucleus of the thalamus (MD) has been implicated in executive functions (such as planning, cognitive control, working memory, and decision-making) because of its significant interconnectivity with the prefrontal cortex (PFC). Yet, whilst the roles of the PFC have been extensively studied, how the MD contributes to these cognitive functions remains relatively unclear. Recently, causal evidence in monkeys has demonstrated that in everyday tasks involving rapid updating (e.g., while learning something new, making decisions, or planning the next move), the MD and frontal cortex are working in close partnership. Furthermore, researchers studying the MD in rodents have been able to probe the underlying mechanisms of this relationship to give greater insights into how the frontal cortex and MD might interact during the performance of these essential tasks. This review summarizes the circuitry and known neuromodulators of the MD, and considers the most recent behavioral, cognitive, and neurophysiological studies conducted in monkeys and rodents; in total, this evidence demonstrates that MD makes a critical contribution to cognitive functions. We propose that communication occurs between the MD and the frontal cortex in an ongoing, fluid manner during rapid cognitive operations, via the means of efference copies of messages passed through transthalamic routes; the conductance of these messages may be modulated by other brain structures interconnected to the MD. This is similar to the way in which other thalamic structures have been suggested to carry out forward modeling associated with rapid motor responding and visual processing. Given this, and the marked thalamic pathophysiology now identified in many neuropsychiatric disorders, we suggest that changes in the different subdivisions of the MD and their interconnections with the cortex could plausibly give rise to a number of the otherwise disparate symptoms (including changes to olfaction and cognitive functioning) that are associated with many different neuropsychiatric disorders. In particular, we will focus here on the cognitive symptoms of schizophrenia and suggest testable hypotheses about how changes to MD-frontal cortex interactions may affect cognitive processes in this disorder

Morphological comparison of visual pathway projections to the temporal lobe from cortical area VI and the tectorecipient zone of the pulvinar nucleus in the tree shrew (Tupaia belangeri).

The secondary visual pathway, from the retina through the superior colliculus and pulvinar nucleus has been linked to spatial attention (Snow et aI., 2009; Arend et aI., 2008) movement planning and motor response to visual stimuli (Wilke et aI. 2010; Grieve et aI. 2000). The tree shrew temporal cortex receives input from the tecto-recipient pulvinar nucleus, composed of the dorsal (PD) and central (PC) subdivisions (Lyon et al. 2003a). We looked at the projections from this pathway to the temporal cortex and compared them to the VI projections to the temporal cortex in the tree shrew. Our focus was to determine if there are differences in these projections that could further define their functional relationships. The characteristics we compared are the layers of termination, the axon and bouton density, the axon arbor shape and branching, axon caliber, bouton size, type and clustering. In order to clearly identify the target temporal lobe areas of projections from VI and the pulvinar, we mapped the architectonic features of the areas on a model brain using a computerized microscope system onto which we then mapped the VI and pulvinar nucleus projections. Our research found that the area to which the axons project defines the morphological characteristics of projections to that target area more than the source of the projection does. This is contrary to existing model of cortical areas receiving driver and modulator projections that have distinct morphological characteristics. We found three projection zones within the TP and TD areas, TP representing the upper peripheral visual field, caudal TD representing the central visual field and rostral TD representing the lower peripheral visual field. Projections to each of these target zones had different morphological characteristics. This evidence would indicate that there are three functions represented in these cortical areas that combine the input of the primary and the secondary visual pathways. The V I and pulvinar nucleus tecto-recipient zone projections to the temporal cortex were thin, dense and moderately to heavily branched. The boutons were mostly small and numerous. V I axons projecting to TP (V 1-TP) and PD axons projecting to TP (PD-TP) have wide arbors of thin axons with extensive branching and many small boutons of mixed boutons en passant and terminal bouton type. V 1 to TP axons are sparser than PO to TP axons and are more likely to give rise to boutons en passant. Pulvinar nucleus projections to caudal ID (PO-TO, PC-cID) also result in wide arbors. These are dense and extensively branched with mixed thin and thick axons and many small to medium sized boutons. VI projections to TD (VI-TD) and pulvinar nucleus projections to rostral TO (PC-rTD) are organized in narrow local arbors of mixed thin and thick caliber axons with sparse to moderate density and branching. Boutons are small to medium sized. V I-TD axon branching is more sparse than PC-rTD axon branching. VI-TD axons have slightly more boutons than PC-rTD axons

The response of cortical neurons to in vivo-like input current: theory and experiment: II. Time-varying and spatially distributed inputs

The response of a population of neurons to time-varying synaptic inputs can show a rich phenomenology, hardly predictable from the dynamical properties of the membrane's inherent time constants. For example, a network of neurons in a state of spontaneous activity can respond significantly more rapidly than each single neuron taken individually. Under the assumption that the statistics of the synaptic input is the same for a population of similarly behaving neurons (mean field approximation), it is possible to greatly simplify the study of neural circuits, both in the case in which the statistics of the input are stationary (reviewed in La Camera et al. in Biol Cybern, 2008) and in the case in which they are time varying and unevenly distributed over the dendritic tree. Here, we review theoretical and experimental results on the single-neuron properties that are relevant for the dynamical collective behavior of a population of neurons. We focus on the response of integrate-and-fire neurons and real cortical neurons to long-lasting, noisy, in vivo-like stationary inputs and show how the theory can predict the observed rhythmic activity of cultures of neurons. We then show how cortical neurons adapt on multiple time scales in response to input with stationary statistics in vitro. Next, we review how it is possible to study the general response properties of a neural circuit to time-varying inputs by estimating the response of single neurons to noisy sinusoidal currents. Finally, we address the dendrite-soma interactions in cortical neurons leading to gain modulation and spike bursts, and show how these effects can be captured by a two-compartment integrate-and-fire neuron. Most of the experimental results reviewed in this article have been successfully reproduced by simple integrate-and-fire model neuron