Sleep spindles in primates: modelling the effects of distinct laminar thalamocortical connectivity in core, matrix, and reticular thalamic circuits

Sleep spindles are associated with the beginning of deep sleep and memory consolidation and are disrupted in schizophrenia and autism. In primates, distinct core and matrix thalamocortical (TC) circuits regulate sleep-spindle activity, through communications that are filtered by the inhibitory thalamic reticular nucleus (TRN) however, little is known about typical TC network interactions and the mechanisms that are disrupted in brain disorders. We developed a primate-specific, circuit-based TC computational model with distinct core and matrix loops that can simulate sleep spindles. We implemented novel multilevel cortical and thalamic mixing, and included local thalamic inhibitory interneurons, and direct layer 5 projections of variable density to TRN and thalamus to investigate the functional consequences of different ratios of core and matrix node connectivity contribution to spindle dynamics. Our simulations showed that spindle power in primates can be modulated based on the level of cortical feedback, thalamic inhibition, and engagement of model core vs. matrix, with the latter having a greater role in spindle dynamics. The study of the distinct spatial and temporal dynamics of core-, matrix-, and mix-generated sleep spindles establishes a framework to study disruption of TC circuit balance underlying deficits in sleep and attentional gating seen in autism and schizophrenia.5R01MH118500-05 REVISED - NIH/National Institute of Mental HealthFirst author draf

Atypical excitatory-inhibitory balance in feedforward and feedback circuits in autism

Interactions between excitatory and inhibitory elements in neural circuits are crucially altered in autism and contribute to its central symptoms. Functionally and neurochemically distinct classes of inhibitory neurons, which express the calcium-binding proteins calbindin (CB), calretinin (CR), and parvalbumin (PV), are distributed differentially between different cortical areas and cortical layers. These neurons modify the influence of the excitatory pathways, carried by myelinated axons, that project to those layers. Excitatory connections that terminate in the middle or deep cortical layers behave similarly to the feedforward pathways that are defined in sensory areas, and provide driving input to the cortex. Pathways that terminate in superficial layers behave as feedback pathways and modulate the activity of the cortex. In order to study excitatory-inhibitory balance in the human cortex we studied the distribution of the three classes of inhibitory neurons and the density of myelinated axons in post-mortem tissue from medial, cingulate, and lateral prefrontal cortices of typically developing individuals and individuals with autism. We separately studied superficial and middle/deep cortical layers in order to distinguish changes that inuence feedback and feedforward pathways. Adults with autism had a significant reduction in the density of CR-expressing inhibitory neurons in both superficial and middle/deep cortical layers in lateral prefrontal cortices. There was a similar trend in medial prefrontal cortices in adults with autism. CR-expressing inhibitory neurons in superficial cortical layers serve a disinhibitory role while those in deep layers may provide modulatory inhibition. We found no significant change in the density of PV-expressing or CBexpressing interneurons in adults with autism in these regions. In individuals with autism there was also a steeper rate of increase in the density of small myelinated axons, which are representative of short-range pathways, across layers during development. These parallel structural changes likely produce opposite functional effects: enhanced short-range feedback pathways terminate in an environment with increased inhibition, while enhanced shortrange feedforward pathways terminate in an environment with reduced inhibition. Together, these changes in laminar structure may significantly affect information processing in the prefrontal cortex in autism.Published versio

Balance of excitation and inhibition in orbitofrontal cortex and potential for disruption in autism

The human orbitofrontal cortex (OFC) is involved in assessing the emotional significance of events and stimuli, emotion based learning, allocation of attentional resources, and social cognition. Little is known about the structure, connectivity and excitatory/inhibitory circuit interactions underlying these diverse functions in human OFC. To fill this gap we used high resolution microscopy, followed by quantitative tracing analysis, to characterize the morphology and distribution of myelinated axons across cortical layers in human OFC at the single axon level, as a proxy of excitatory pathways. In the same regions, we also examined the laminar distribution of neurochemically- and functionally-distinct inhibitory neurons that express calcium-binding proteins parvalbumin (PV), calbindin (CB), and calretinin (CR). Associations of myelinated axons with distinct inhibitory neurons changed across layers and provided a proxy for the study of the excitatory/inhibitory ratio in OFC. We found that density of myelinated axons increased consistently towards layer VI, while average axon diameter did not change significantly. Inhibitory CR-positive neurons were mostly found in layer II, the layer with the lowest density of myelinated axons. CB-positive inhibitory neurons were most dense in layer II and upper layer III. PV-positive inhibitory neurons were mostly found in the middle/deep layers, especially lower layer III, among a dense plexus of myelinated axons, some of which also expressed PV, presumably coming from the thalamus. The balance between excitation and inhibition in OFC is at the core of OFC function. The OFC gets an overview of the sensory environment through feedforward cortical inputs and assesses the emotional significance of events, based on robust feedback input from the amygdala, in processes that are disrupted in autism spectrum disorder (ASD). We previously showed that in individuals with ASD, excitatory OFC pathways exhibit overall thinning of the myelin sheath of axons, which likely affects conduction velocity and neurotransmission. This suggests laminar-specific changes in the ratio of excitation/inhibition in OFC of individuals with ASD, and may provide the anatomic basis for disrupted transmission of signals for emotions.Published versio

Relay of affective stimuli from amygdala to thalamus parallels sensory pathways

The amygdala, the emotional sensor of the brain, is strongly connected with the posterior orbitofrontal cortex (pOFC), forming a pathway activated by reward learning. In addition, the amygdala innervates neurons in the mediodorsal thalamic nucleus (MD) that project to pOFC, forming a second, indirect route for the amygdala to inuence the pOFC sector of the prefrontal cortex. The indirect pathway that connects the amygdala and pOFC through the thalamus may be similar to sensory pathways connecting peripheral receptors with sensory cortices through sensory relay thalamic nuclei. The indirect pathway is morphologically distinct from the direct pathway; amygdalar pathway terminals in MD are larger than those in the pOFC, and likely derive from separate neuronal populations in the amygdala (Timbie and Barbas, Society for Neuroscience, 2013; J Neurosci, 2015). The synaptic interactions and potential specializations of amygdalar terminals in MD have not yet been described in comparison to other thalamic afferents. We addressed this issue by labeling amygdalar axons in MD in rhesus monkeys and compared them with retinal axons terminating in the lateral geniculate nucleus (LGN). We studied axon terminations in MD and LGN using serial section electron microscopy and analyzed pre- and post-synaptic elements by morphology. All amygdalar terminals in MD and retinal ganglion terminals in LGN contained multiple mitochondria, and were classed as round, large (RL) boutons. Amygdalar and retinal RL boutons contained excitatory type vesicles and formed several asymmetric (excitatory) synapses with dendrites of thalamocortical relay neurons and dendrites of inhibitory interneurons. In a significant proportion of these multi-synaptic arrangements, the inhibitory dendrites contained vesicles and formed symmetric synapses with the dendrite of the thalamocortical neuron. These novel findings reveal that amygdalar terminals in MD form synaptic triads, reminiscent of those found in sensory thalamic relay nuclei, like LGN. Our findings suggest that amygdalar inputs to MD can drive signals to cortex, ensuring efficient transmission of salient emotional information, akin to sensory thalamic relays.Published versio