Subcortical Inputs Research Articles

Understanding subcortical projections to the lateral posterior thalamic nucleus and its subregions using retrograde neural tracing.

The rat lateral posterior thalamic nucleus (LP) is composed of the rostromedial (LPrm), lateral (LPl), and caudomedial parts, with LPrm and LPl being areas involved in information processing within the visual cortex. Nevertheless, the specific differences in the subcortical projections to the LPrm and LPl remain elusive. In this study, we aimed to reveal the subcortical regions that project axon fibers to the LPl and LPrm using a retrograde neural tracer, Fluorogold (FG). After FG injection into the LPrm or LPl, the area was visualized immunohistochemically. Retrogradely labeled neurons from the LPrm were distributed in the retina and the region from the diencephalon to the medulla oblongata. Diencephalic labeling was found in the reticular thalamic nucleus (Rt), zona incerta (ZI), ventral lateral geniculate nucleus (LGv), intergeniculate leaflet (IGL), and hypothalamus. In the midbrain, prominent labeling was found in the periaqueductal gray (PAG) and deep layers of the superior colliculus. Additionally, retrograde labeling was observed in the cerebellar and trigeminal nuclei. When injected into the LPl, several cell bodies were labeled in the visual-related regions, including the retina, LGv, IGL, and olivary pretectal nucleus (OPT), as well as in the Rt and anterior pretectal nucleus (APT). Less labeling was found in the cerebellum and medulla oblongata. When the number of retrogradely labeled neurons from the LPrm or LPl was compared as a percentage of total subcortical labeling, a larger percentage of subcortical inputs to the LPl included projections from the APT, OPT, and Rt, whereas a large proportion of subcortical inputs to the LPrm originated from the ZI, reticular formation, and PAG. These results suggest that LPrm not only has visual but also multiple sensory-and motor-related functions, whereas the LPl takes part in a more visual-specific role. This study enhances our understanding of subcortical neural circuits in the thalamus and may contribute to our exploration of the mechanisms and disorders related to sensory perception and sensory-motor integration.

Convergent direct and indirect cortical streams shape avoidance decisions in mice via the midline thalamus

Current concepts of corticothalamic organization in the mammalian brain are mainly based on sensory systems, with less focus on circuits for higher-order cognitive functions. In sensory systems, first-order thalamic relays are driven by subcortical inputs and modulated by cortical feedback, while higher-order relays receive strong excitatory cortical inputs. The applicability of these principles beyond sensory systems is uncertain. We investigated mouse prefronto-thalamic projections to the midline thalamus, revealing distinct top-down control. Unlike sensory systems, this pathway relies on indirect modulation via the thalamic reticular nucleus (TRN). Specifically, the prelimbic area, which influences emotional and motivated behaviors, impacts instrumental avoidance responses through direct and indirect projections to the paraventricular thalamus. Both pathways promote defensive states, but the indirect pathway via the TRN is essential for organizing avoidance decisions through disinhibition. Our findings highlight intra-thalamic circuit dynamics that integrate cortical cognitive signals and their role in shaping complex behaviors.

Modulation of contextual fear acquisition and extinction by acute and chronic relaxin-3 receptor (RXFP3) activation in the rat retrosplenial cortex

The retrosplenial cortex (RSC) plays a central role in processing contextual fear conditioning. In addition to corticocortical and thalamocortical projections, the RSC receives subcortical inputs, including a substantial projection from the nucleus incertus in the pontine tegmentum. This GABAergic projection contains the neuropeptide, relaxin-3 (RLN3), which inhibits target neurons via its Gi/o-protein-coupled receptor, RXFP3. To assess this peptidergic system role in contextual fear conditioning, we bilaterally injected the RSC of adult rats with an adeno-associated-virus (AAV), expressing the chimeric RXFP3 agonist R3/I5 or a control AAV, and subjected them to contextual fear conditioning. The R3/I5 injected rats did not display any major differences to control-injected and naïve rats but displayed a significantly delayed extinction. Subsequently, we employed acute bilateral injections of the specific RXFP3 agonist peptide, RXFP3-Analogue 2 (A2), into RSC. While the administration of A2 before each extinction trial had no impact on the extinction process, treatment with A2 before each acquisition trial resulted in delayed extinction. In related anatomical studies, we detected an enrichment of RLN3-immunoreactive nerve fibers in deep layers of the RSC, and a higher level of co-localization of RXFP3 mRNA with vesicular GABA transporter (vGAT) mRNA than with vesicular glutamate transporter-1 (vGLUT1) mRNA across the RSC, consistent with an effect of RLN3/RXFP3 signalling on the intrinsic, inhibitory circuits within the RSC. These findings suggest that contextual conditioning processes in the RSC involve, in part, RLN3 afferent modulation of local inhibitory neurons that provides a stronger memory acquisition which, in turn, retards the extinction process.

Speech decoding using cortical and subcortical electrophysiological signals.

Language impairments often result from severe neurological disorders, driving the development of neural prosthetics utilizing electrophysiological signals to restore comprehensible language. Previous decoding efforts primarily focused on signals from the cerebral cortex, neglecting subcortical brain structures' potential contributions to speech decoding in brain-computer interfaces. In this study, stereotactic electroencephalography (sEEG) was employed to investigate subcortical structures' role in speech decoding. Two native Mandarin Chinese speakers, undergoing sEEG implantation for epilepsy treatment, participated. Participants read Chinese text, with 1-30, 30-70, and 70-150 Hz frequency band powers of sEEG signals extracted as key features. A deep learning model based on long short-term memory assessed the contribution of different brain structures to speech decoding, predicting consonant articulatory place, manner, and tone within single syllable. Cortical signals excelled in articulatory place prediction (86.5% accuracy), while cortical and subcortical signals performed similarly for articulatory manner (51.5% vs. 51.7% accuracy). Subcortical signals provided superior tone prediction (58.3% accuracy). The superior temporal gyrus was consistently relevant in speech decoding for consonants and tone. Combining cortical and subcortical inputs yielded the highest prediction accuracy, especially for tone. This study underscores the essential roles of both cortical and subcortical structures in different aspects of speech decoding.

Micropopulation mapping of the mouse parafascicular nucleus connections reveals diverse input-output motifs.

In primates, including humans, the centromedian/parafascicular (CM-Pf) complex is a key thalamic node of the basal ganglia system. Deep brain stimulation in CM-Pf has been applied for the treatment of motor disorders such as Parkinson's disease or Tourette syndrome. Rodents have become widely used models for the study of the cellular and genetic mechanisms of these and other motor disorders. However, the equivalence between the primate CM-Pf and the nucleus regarded as analogous in rodents (Parafascicular, Pf) remains unclear. Here, we analyzed the neurochemical architecture and carried out a brain-wide mapping of the input-output motifs in the mouse Pf at micropopulation level using anterograde and retrograde labeling methods. Specifically, we mapped and quantified the sources of cortical and subcortical input to different Pf subregions, and mapped and compared the distribution and terminal structure of their axons. We found that projections to Pf arise predominantly (>75%) from the cerebral cortex, with an unusually strong (>45%) Layer 5b component, which is, in part, contralateral. The intermediate layers of the superior colliculus are the main subcortical input source to Pf. On its output side, Pf neuron axons predominantly innervate the striatum. In a sparser fashion, they innervate other basal ganglia nuclei, including the subthalamic nucleus (STN), and the cerebral cortex. Differences are evident between the lateral and medial portions of Pf, both in chemoarchitecture and in connectivity. Lateral Pf axons innervate territories of the striatum, STN and cortex involved in the sensorimotor control of different parts of the contralateral hemibody. In contrast, the mediodorsal portion of Pf innervates oculomotor-limbic territories in the above three structures. Our data thus indicate that the mouse Pf consists of several neurochemically and connectively distinct domains whose global organization bears a marked similarity to that described in the primate CM-Pf complex.

The impact of HCN4 channels on CNS brain networks as a new target in pain development.

While it is well established that the isoform 2 of the hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN2) plays an important role in the development and maintenance of pain, the role of the closely related HCN4 isoform in the processing of nociceptive signals is not known. HCN4 channels are highly expressed in the thalamus, a region important for stimulus transmission and information processing. We used a brain-specific HCN4-knockout mouse line (HCN4-KO) to explore the role of HCN4 channels in acute nociceptive processing using several behavioral tests as well as a multimodal magnetic resonance imaging (MRI) approach. Functional MRI (fMRI) brain responses were measured during acute peripheral thermal stimulation complemented by resting state (RS) before and after stimulation. The data were analyzed by conventional and graph-theoretical approaches. Finally, high-resolution anatomical brain data were acquired. HCN4-KO animals showed a central thermal, but not a mechanical hypersensitivity in behavioral experiments. The open field analysis showed no significant differences in motor readouts between HCN4-KO and controls but uncovered increased anxiety in the HCN4-KO mice. Thermal stimulus-driven fMRI (s-fMRI) data revealed increased response volumes and response amplitudes for HCN4-KO, most pronounced at lower stimulation temperatures in the subcortical input, the amygdala as well as in limbic/hippocampal regions, and in the cerebellum. These findings could be cross-validated by graph-theoretical analyses. Assessment of short-term RS before and after thermal stimulation revealed that stimulation-related modulations of the functional connectivity only occurred in control animals. This was consistent with the finding that the hippocampus was found to be smaller in HCN4-KO. In summary, the deletion of HCN4 channels impacts on processing of acute nociception, which is remarkably manifested as a thermal hypersensitive phenotype. This was mediated by the key regions hypothalamus, somatosensory cortex, cerebellum and the amygdala. As consequence, HCN4-KO mice were more anxious, and their brain-wide RS functional connectivity could not be modulated by thermal nociceptive stimulation.

Neural patterns of conscious visual awareness in the Riddoch syndrome

The Riddoch syndrome is one in which patients blinded by lesions to their primary visual cortex can consciously perceive visual motion in their blind field, an ability that correlates with activity in motion area V5. Our assessment of the characteristics of this syndrome in patient ST, using multimodal MRI, showed that: 1. ST’s V5 is intact, receives direct subcortical input, and decodable neural patterns emerge in it only during the conscious perception of visual motion; 2. moving stimuli activate medial visual areas but, unless associated with decodable V5 activity, they remain unperceived; 3. ST’s high confidence ratings when discriminating motion at chance levels, is associated with inferior frontal gyrus activity. Finally, we report that ST’s Riddoch Syndrome results in hallucinatory motion with hippocampal activity as a correlate. Our results shed new light on perceptual experiences associated with this syndrome and on the neural determinants of conscious visual experience.

Selective refinement of glutamate and GABA synapses on dorsal raphe 5-HT neurons during postnatal life.

Serotonin (5-hydroxytryptamine, 5-HT) neurons are implicated in the etiology and therapeutics of anxiety and depression. Critical periods of vulnerability during brain development enable maladaptive mechanisms to produce detrimental consequences on adult mood and emotional responses. 5-HT plays a crucial role in these mechanisms; however, little is known about how synaptic inputs and modulatory systems that shape the activity of early 5-HT networks mature during postnatal development. We investigated in mice the postnatal trajectory of glutamate and GABA synaptic inputs to dorsal raphe nucleus (DRN) 5-HT neurons, the main source of forebrain 5-HT. High-resolution quantitative analyses with array tomography and ex vivo electrophysiology indicate that cortical glutamate and subcortical GABA synapses undergo a profound refinement process after the third postnatal week, whereas subcortical glutamate inputs do not. This refinement of DRN inputs is not accompanied by changes in 5-HT1A receptor-mediated inhibition over 5-HT neurons. Our study reveals a precise developmental pattern of synaptic refinement of DRN excitatory and inhibitory afferents, when 5-HT-related inhibitory mechanisms are in place. These findings contribute to the understanding of neurodevelopmental vulnerability to psychiatric disorders. This article has an associated 'The people behind the papers' interview.

Subcortical glutamatergic inputs exhibit a Hebbian form of long-term potentiation in the dentate gyrus

The hippocampus receives glutamatergic and GABAergic inputs from subcortical regions. Despite the important roles of these subcortical inputs in the regulation of hippocampal circuit, it has not been explored whether associative activation of the subcorticohippocampal pathway induces Hebbian plasticity of subcortical inputs. Here, we demonstrate that the hypothalamic supramammillary nucleus (SuM) to the dentate granule cell (GC) synapses, which co-release glutamate and GABA, undergo associative long-term potentiation (LTP) of glutamatergic, but not GABAergic, co-transmission. This LTP is induced by pairing of SuM inputs with GC spikes. We found that this Hebbian LTP is input-specific, requires NMDA receptors and CaMKII activation, and is expressed postsynaptically. By the net increase in excitatory drive of SuM inputs following LTP induction, associative inputs of SuM and the perforant path effectively discharge GCs. Our results highlight the important role of associative plasticity at SuM-GC synapses in the regulation of dentate gyrus activity and for the encoding of SuM-related information.

Cortico-thalamocortical interactions for learning, memory and decision-making.

The thalamus and cortex are interconnected both functionally and anatomically and share a common developmental trajectory. Interactions between the mediodorsal thalamus (MD) and different parts of the prefrontal cortex are essential in cognitive processes, such as learning and adaptive decision-making. Cortico-thalamocortical interactions involving other dorsal thalamic nuclei, including the anterior thalamus and pulvinar, also influence these cognitive processes. Our work, and that of others, indicates a crucial influence of these interdependent cortico-thalamocortical neural networks that contributes actively to the processing of information within the cortex. Each of these thalamic nuclei also receives potent subcortical inputs that are likely to provide additional influences on their regulation of cortical activity. Here, we highlight our current neuroscientific research aimed at establishing when cortico-MD thalamocortical neural network communication is vital within the context of a rapid learning and memory discrimination task. We are collecting evidence of MD-prefrontal cortex neural network communication in awake, behaving male rhesus macaques. Given the prevailing evidence, further studies are needed to identify both broad and specific mechanisms that govern how the MD, anterior thalamus and pulvinar cortico-thalamocortical interactions support learning, memory and decision-making. Current evidence shows that the MD (and the anterior thalamus) are crucial for frontotemporal communication, and the pulvinar is crucial for frontoparietal communication. Such work is crucial to advance our understanding of the neuroanatomical and physiological bases of these brain functions in humans. In turn, this might offer avenues to develop effective treatment strategies to improve the cognitive deficits often observed in many debilitating neurological disorders and diseases and in neurodegeneration.

Reproducible protocol to obtain and measure first-order relay human thalamic white-matter tracts

The “primary” or “first-order relay” nuclei of the thalamus feed the cerebral cortex with information about ongoing activity in the environment or the subcortical motor systems. Because of the small size of these nuclei and the high specificity of their input and output pathways, new imaging protocols are required to investigate thalamocortical interactions in human perception, cognition and language. The goal of the present study was twofold: I) to develop a reconstruction protocol based on in vivo diffusion MRI to extract and measure the axonal fiber tracts that originate or terminate specifically in individual first-order relay nuclei; and, II) to test the reliability of this reconstruction protocol. In left and right hemispheres, we investigated the thalamocortical/corticothalamic axon bundles linking each of the first-order relay nuclei and their main cortical target areas, namely, the lateral geniculate nucleus (optic radiation), the medial geniculate nucleus (acoustic radiation), the ventral posterior nucleus (somatosensory radiation) and the ventral lateral nucleus (motor radiation). In addition, we examined the main subcortical input pathway to the ventral lateral posterior nucleus, which originates in the dentate nucleus of the cerebellum. Our protocol comprised three components: defining regions-of-interest; preprocessing diffusion data; and modeling white-matter tracts and tractometry. We then used computation and test-retest methods to check whether our protocol could reliably reconstruct these tracts of interest and their profiles. Our results demonstrated that the protocol had nearly perfect computational reproducibility and good-to-excellent test-retest reproducibility. This new protocol may be of interest for both basic human brain neuroscience and clinical studies and has been made publicly available to the scientific community.

Age-Related Changes in Micro Brain Characteristics Based on Relaxed Mean-Field Model.

Brain health is an important research direction of neuroscience. In addition to the effects of diseases, we cannot ignore the negative effect of aging on brain health. There have been many studies on brain aging, but only a few have used dynamic models to analyze differences in micro brain characteristics in healthy people. In this article, we use the relaxed mean-field model (rMFM) to study the effects of normal aging. Two main parameters of this model are the recurrent connection strength and subcortical input strength. The sensitivity of the rMFM to the initial values of the parameters has not been fully discussed in previous research. We examine this issue through repeated numerical experiments and obtain a reasonable initial parameter range for this model. Differences in recurrent connection strength and subcortical input strength due to aging have also not been studied previously. We use statistical methods to find the regions of interest (ROIs) exhibiting significant differences between young and old groups. Further, we carry out a difference analysis on the process of change of these ROIs on a more detailed timescale. We find that even with the same final results, the trends of change in these ROIs are different. This shows that to develop possible methods to prevent or delay brain damage due to aging, more attention needs to be paid to the trends of change of different ROIs, not just the final results.

Brain-wide mapping of inputs to the mouse lateral posterior (LP/Pulvinar) thalamus-anterior cingulate cortex network.

The rodent homolog of the primate pulvinar, the lateral posterior (LP) thalamus, is extensively interconnected with multiple cortical areas. While these cortical interactions can span the entire LP, subdivisions of the LP are characterized by differential connections with specific cortical regions. In particular, the medial LP has reciprocal connections with frontoparietal cortical areas, including the anterior cingulate cortex (ACC). The ACC plays an integral role in top‐down sensory processing and attentional regulation, likely exerting some of these functions via the LP. However, little is known about how ACC and LP interact, and about the information potentially integrated in this reciprocal network. Here, we address this gap by employing a projection‐specific monosynaptic rabies tracing strategy to delineate brain‐wide inputs to bottom‐up LP→ACC and top‐down ACC→LP neurons. We find that LP→ACC neurons receive inputs from widespread cortical regions, including primary and higher order sensory and motor cortical areas. LP→ACC neurons also receive extensive subcortical inputs, particularly from the intermediate and deep layers of the superior colliculus (SC). Sensory inputs to ACC→LP neurons largely arise from visual cortical areas. In addition, ACC→LP neurons integrate cross‐hemispheric prefrontal cortex inputs as well as inputs from higher order medial cortex. Our brain‐wide anatomical mapping of inputs to the reciprocal LP‐ACC pathways provides a roadmap for understanding how LP and ACC communicate different sources of information to mediate attentional control and visuomotor functions.

Rapid processing of threatening faces in the amygdala of nonhuman primates: subcortical inputs and dual roles.

A subcortical pathway through the superior colliculus and pulvinar has been proposed to provide the amygdala with rapid but coarse visual information about emotional faces. However, evidence for short-latency, facial expression-discriminating responses from individual amygdala neurons is lacking; even if such a response exists, how it might contribute to stimulus detection is unclear. Also, no definitive anatomical evidence is available for the assumed pathway. Here we showed that ensemble responses of amygdala neurons in monkeys carried robust information about open-mouthed, presumably threatening, faces within 50ms after stimulus onset. This short-latency signal was not found in the visual cortex, suggesting a subcortical origin. Temporal analysis revealed that the early response contained excitatory and suppressive components. The excitatory component may be useful for sending rapid signals downstream, while the sharpening of the rising phase of later-arriving inputs (presumably from the cortex) by the suppressive component might improve the processing of facial expressions over time. Injection of a retrograde trans-synaptic tracer into the amygdala revealed presumed monosynaptic labeling in the pulvinar and disynaptic labeling in the superior colliculus, including the retinorecipient layers. We suggest that the early amygdala responses originating from the colliculo-pulvino-amygdalar pathway play dual roles in threat detection.

Unilateral transfemoral amputees exhibit altered strength and dynamics of muscular co-activation modulated by visual feedback

Objective. Somatosensory perception is disrupted in patients with a lower limb amputation. This increases the difficulty to maintain balance and leads to the development of neuromuscular adjustments. We investigated how these adjustments are reflected in the co-activation of lower body muscles and are modulated by visual feedback. Approach. We measured electromyography (EMG) signals of muscles from the trunk (erector spinae and obliquus external), and the lower intact/dominant leg (tibialis anterior and medial gastrocnemius) in 11 unilateral transfemoral amputees and 11 age-matched able-bodied controls during 30 s of upright standing with and without visual feedback. Muscle synergies involved in balance control were investigated using wavelet coherence analysis. We focused on seven frequencies grouped in three frequency bands, a low-frequency band (7.56 and 19.86 Hz) representing more sub-cortical and spinal inputs to the muscles, a mid-frequency band (38.26 and 62.63 Hz) representing more cortical inputs, and a high-frequency band (92.90, 129 and 170.90 Hz) associated with synchronizing motor unit action potentials. Further, the dynamics of changes in intermuscular coupling over time were quantified using the Entropic Half-Life. Main results. Amputees exhibited lower coherency values when vision was removed at 7.56 Hz for the muscle pair of the lower leg. At this frequency, the coherency values of the amputee group also differed from controls for the eyes closed condition. Controls and amputees exhibited opposite coherent behaviors with visual feedback at 7.56 Hz. For the eyes open condition at 129 Hz, the coherency values of amputees and controls differed for the muscle pair of the trunk, and at 170.90 Hz for the muscle pair of the lower leg. Amputees exhibited different dynamics of muscle co-activation at the low frequency band when vision was available. Significance. Altogether, these findings point to the development of neuromuscular adaptations reflected in the strength and dynamics of muscular co-activation.

Muscarinic Acetylcholine Receptor Localization on Distinct Excitatory and Inhibitory Neurons Within the ACC and LPFC of the Rhesus Monkey.

Acetylcholine (ACh) can act on pre- and post-synaptic muscarinic receptors (mAChR) in the cortex to influence a myriad of cognitive processes. Two functionally-distinct regions of the prefrontal cortex—the lateral prefrontal cortex (LPFC) and the anterior cingulate cortex (ACC)—are differentially innervated by ascending cholinergic pathways yet, the nature and organization of prefrontal-cholinergic circuitry in primates are not well understood. Using multi-channel immunohistochemical labeling and high-resolution microscopy, we found regional and laminar differences in the subcellular localization and the densities of excitatory and inhibitory subpopulations expressing m1 and m2 muscarinic receptors, the two predominant cortical mAChR subtypes, in the supragranular layers of LPFC and ACC in rhesus monkeys (Macaca mulatta). The subset of m1+/m2+ expressing SMI-32+ pyramidal neurons labeled in layer 3 (L3) was denser in LPFC than in ACC, while m1+/m2+ SMI-32+ neurons co-expressing the calcium-binding protein, calbindin (CB) was greater in ACC. Further, we found between-area differences in laminar m1+ dendritic expression, and m2+ presynaptic localization on cortico-cortical (VGLUT1+) and sub-cortical inputs (VGLUT2+), suggesting differential cholinergic modulation of top-down vs. bottom-up inputs in the two areas. While almost all inhibitory interneurons—identified by their expression of parvalbumin (PV+), CB+, and calretinin (CR+)—expressed m1+, the localization of m2+ differed by subtype and area. The ACC exhibited a greater proportion of m2+ inhibitory neurons compared to the LPFC and had a greater density of presynaptic m2+ localized on inhibitory (VGAT+) inputs targeting proximal somatodendritic compartments and axon initial segments of L3 pyramidal neurons. These data suggest a greater capacity for m2+-mediated cholinergic suppression of inhibition in the ACC compared to the LPFC. The anatomical localization of muscarinic receptors on ACC and LPFC micro-circuits shown here contributes to our understanding of diverse cholinergic neuromodulation of functionally-distinct prefrontal areas involved in goal-directed behavior, and how these interactions maybe disrupted in neuropsychiatric and neurological conditions.

Distinct “driving” versus “modulatory” influences of different visual corticothalamic pathways

Higher-order (HO) thalamic nuclei interact extensively and reciprocally with the cerebral cortex. These corticothalamic (CT) interactions are thought to be important for sensation and perception, attention, and many other important brain functions. CT projections to HO thalamic nuclei, such as the visual pulvinar, originate from two different excitatory populations in cortical layers 5 and 6, whereas first-order nuclei (such as the dorsolateral geniculate nucleus; dLGN) only receive layer 6 CT input. It has been proposed that these layer 5 and layer 6 CT pathways have different functional influences on the HO thalamus, but this has never been directly tested. By optogenetically inactivating different CT populations in the primary visual cortex (V1) and recording single-unit activity from V1, dLGN, and pulvinar of awake mice, we demonstrate that layer 5, but not layer 6, CT projections drive visual responses in the pulvinar, even while both pathways provide retinotopic, baseline excitation to their thalamic targets. Inactivating the superior colliculus also suppressed visual responses in the same subregion of the pulvinar, demonstrating that cortical layer 5 and subcortical inputs both contribute to HO visual thalamic activity-even at the level of putative single neurons. Altogether, these results indicate a functional division of "driver" and "modulator" CT pathways from V1 to the visual thalamus invivo.

Hypothalamic Glutamate/GABA Cotransmission Modulates Hippocampal Circuits and Supports Long-Term Potentiation.

Subcortical input engages in cortico-hippocampal information processing. Neurons of the hypothalamic supramammillary nucleus (SuM) innervate the dentate gyrus (DG) by coreleasing two contrasting fast neurotransmitters, glutamate and GABA, and thereby support spatial navigation and contextual memory. However, the synaptic mechanisms by which SuM neurons regulate the DG activity and synaptic plasticity are not well understood. The DG comprises excitatory granule cells (GCs) as well as inhibitory interneurons (INs). Combining optogenetic, electrophysiological, and pharmacological approaches, we demonstrate that the SuM input differentially regulates the activities of different DG neurons in mice of either sex via distinct synaptic mechanisms. Although SuM activation results in synaptic excitation and inhibition in all postsynaptic cells, the ratio of these two components is variable and cell type-dependent. Specifically, dendrite-targeting INs receive predominantly synaptic excitation, whereas soma-targeting INs and GCs receive primarily synaptic inhibition. Although SuM excitation alone is insufficient to excite GCs, it enhances the GC spiking precision and reduces the latencies in response to excitatory drives. Furthermore, SuM excitation enhances the GC spiking in response to the cortical input, thereby promoting induction of long-term potentiation at cortical-GC synapses. Collectively, these findings provide physiological significance of the cotransmission of glutamate/GABA by SuM neurons in the DG network.SIGNIFICANCE STATEMENT The cortical-hippocampal pathways transfer mnemonic information during memory acquisition and retrieval, whereas subcortical input engages in modulation of communication between the cortex and hippocampus. The supramammillary nucleus (SuM) neurons of the hypothalamus innervate the dentate gyrus (DG) by coreleasing glutamate and GABA onto granule cells (GCs) and interneurons and support memories. However, how the SuM input regulates the activity of various DG cell types and thereby contributes to synaptic plasticity remains unexplored. Combining optogenetic and electrophysiological approaches, we demonstrate that the SuM input differentially regulates DG cell dynamics and consequently enhances GC excitability as well as synaptic plasticity at cortical input-GC synapses. Our findings highlight a significant role of glutamate/GABA cotransmission in regulating the input-output dynamics of DG circuits.

Laser-Induced Apoptosis of Corticothalamic Neurons in Layer VI of Auditory Cortex Impact on Cortical Frequency Processing.

Corticofugal projections outnumber subcortical input projections by far. However, the specific role for signal processing of corticofugal feedback is still less well understood in comparisonto the feedforward projection. Here, we lesioned corticothalamic (CT) neurons in layers V and/or VI of the auditory cortex of Mongolian gerbils by laser-induced photolysis to investigate their contribution to cortical activation patterns. We have used laminar current-source density (CSD) recordings of tone-evoked responses and could show that, particularly, lesion of CT neurons in layer VI affected cortical frequency processing. Specifically, we found a decreased gain of best-frequency input in thalamocortical (TC)-recipient input layers that correlated with the relative lesion of layer VI neurons, but not layer V neurons. Using cortical silencing with the GABAa-agonist muscimol and layer-specific intracortical microstimulation (ICMS), we found that direct activation of infragranular layers recruited a local recurrent cortico-thalamo-cortical loop of synaptic input. This recurrent feedback was also only interrupted when lesioning layer VI neurons, but not cells in layer V. Our study thereby shows distinct roles of these two types of CT neurons suggesting a particular impact of CT feedback from layer VI to affect the local feedforward frequency processing in auditory cortex.

Different roles of subcortical inputs in V1 responses to luminance and contrast.

Cells in the primary visual cortex (V1) generally respond weakly to large uniform luminance stimuli. Only a subset of V1 cells is thought to encode uniform luminance information. In natural scenes, local luminance is an important feature for defining an object that varies and coexists with local spatial contrast. However, the strategies used by V1 cells to encode local mean luminance for spatial contrast stimuli remain largely unclear. Here, using extracellular recordings in anesthetized cats, we investigated the responses of V1 cells by comparing with those of retinal ganglion (RG) cells and lateral geniculate nucleus (LGN) cells to simultaneous and rapid changes in luminance and spatial contrast. Almost all V1 cells exhibited a strong monotonic increasing luminance tuning when they were exposed to high spatial contrast. Thus, V1 cells encode the luminance carried by spatial contrast stimuli with the monotonically increasing response function. Moreover, high contrast decreased luminance tuning of OFF cells but increased that of in ON cells in RG and LGN. The luminance and contrast tunings of LGN ON cells were highly separable as V1 cells, whereas those of LGN OFF cells were lowly separable. These asymmetrical effects of spatial contrast on ON/OFF channels might underlie the robust ability of V1 cells to perform luminance tuning when exposed to spatial contrast stimuli.