Divergent midbrain circuits orchestrate escape and freezing responses to looming stimuli in mice.

Animals respond to environmental threats, e.g. looming visual stimuli, with innate defensive behaviors such as escape and freezing. The key neural circuits that participate in the generation of such dimorphic defensive behaviors remain unclear. Here we show that the dimorphic behavioral patterns triggered by looming visual stimuli are mediated by parvalbumin-positive (PV+) projection neurons in mouse superior colliculus (SC). Two distinct groups of SC PV+ neurons form divergent pathways to transmit threat-relevant visual signals to neurons in the parabigeminal nucleus (PBGN) and lateral posterior thalamic nucleus (LPTN). Activations of PV+ SC-PBGN and SC-LPTN pathways mimic the dimorphic defensive behaviors. The PBGN and LPTN neurons are co-activated by looming visual stimuli. Bilateral inactivation of either nucleus results in the defensive behavior dominated by the other nucleus. Together, these data suggest that the SC orchestrates dimorphic defensive behaviors through two separate tectofugal pathways that may have interactions.

Do the anterior and lateral thalamic nuclei make distinct contributions to spatial representation and memory?

The anterior and lateral thalamus has long been considered to play an important role in spatial and mnemonic cognitive functions; however, it remains unclear whether each region makes a unique contribution to spatial information processing. We begin by reviewing evidence from anatomical studies and electrophysiological recordings which suggest that at least one of the functions of the anterior thalamus is to guide spatial orientation in relation to a global or distal spatial framework, while the lateral thalamus serves to guide behavior in relation to a local or proximal framework. We conclude by reviewing experimental work using targeted manipulations (lesion or neuronal silencing) of thalamic nuclei during spatial behavior and single-unit recordings from neuronal representations of space. Our summary of this literature suggests that although the evidence strongly supports a working model of spatial information processing involving the anterior thalamus, research regarding the role of the lateral thalamus is limited and requires further attention. We therefore identify a number of major gaps in this research and suggest avenues of future study that could potentially solidify our understanding of the relative roles of anterior and lateral thalamic regions in spatial representation and memory.

Visual input to the mouse lateral posterior and posterior thalamic nuclei: photoreceptive origins and retinotopic order.

KEY POINTS: The lateral posterior and posterior thalamic nuclei have been implicated in aspects of visually guided behaviour and reflex responses to light, including those dependent on melanopsin photoreception. Here we investigated the extent and basic properties of visually evoked activity across the mouse lateral posterior and posterior thalamus. We show that a subset of retinal projections to these regions derive from melanopsin-expressing retinal ganglion cells and find many cells that exhibit melanopsin-dependent changes in firing. We also show that subsets of cells across these regions integrate signals from both eyes in various ways and that, within the lateral posterior thalamus, visual responses are retinotopically ordered. ABSTRACT: In addition to the primary thalamocortical visual relay in the lateral geniculate nuclei, a number of other thalamic regions contribute to aspects of visual processing. Thus, the lateral posterior thalamic nuclei (LP/pulvinar) appear important for various functions including determining visual saliency, visually guided behaviours and, alongside dorsal portions of the posterior thalamic nuclei (Po), multisensory processing of information related to aversive stimuli. However, despite the growing importance of mice as a model for understanding visual system organisation, at present we know very little about the basic visual response properties of cells in the mouse LP or Po. Prompted by earlier suggestions that melanopsin photoreception might be important for certain functions of these nuclei, we first employ specific viral tracing to show that a subset of retinal projections to the LP derive from melanopsin-expressing retinal ganglion cells. We next use multielectrode electrophysiology to demonstrate that LP and dorsal Po cells exhibit a variety of responses to simple visual stimuli including two distinct classes that express melanopsin-dependent changes in firing (together comprising ∼25% of neurons we recorded). We also show that subgroups of LP/Po cells integrate signals from both eyes in various ways and that, within the LP, visual responses are retinotopically ordered. Together our data reveal a diverse population of visually responsive neurons across the LP and dorsal Po whose properties align with some of the established functions of these nuclei and suggest new possible routes through which melanopsin photoreception could contribute to reflex light responses and/or higher order visual processing.

Processing of visually evoked innate fear by a non-canonical thalamic pathway.

The ability of animals to respond to life-threatening stimuli is essential for survival. Although vision provides one of the major sensory inputs for detecting threats across animal species, the circuitry underlying defensive responses to visual stimuli remains poorly defined. Here, we investigate the circuitry underlying innate defensive behaviours elicited by predator-like visual stimuli in mice. Our results demonstrate that neurons in the superior colliculus (SC) are essential for a variety of acute and persistent defensive responses to overhead looming stimuli. Optogenetic mapping revealed that SC projections to the lateral posterior nucleus (LP) of the thalamus, a non-canonical polymodal sensory relay, are sufficient to mimic visually evoked fear responses. In vivo electrophysiology experiments identified a di-synaptic circuit from SC through LP to the lateral amygdale (Amg), and lesions of the Amg blocked the full range of visually evoked defensive responses. Our results reveal a novel collicular-thalamic-Amg circuit important for innate defensive responses to visual threats.

Effect of spinal manipulation thrust duration on trunk mechanical activation thresholds of nociceptive-specific lateral thalamic neurons.

OBJECTIVE: The objective of this preliminary study was to determine if high-velocity, low-amplitude spinal manipulation (HVLA-SM) thrust duration alters mechanical trunk activation thresholds of nociceptive-specific (NS) lateral thalamic neurons. METHODS: Extracellular recordings were obtained from 18 NS neurons located in 2 lateral thalamic nuclei (ventrolateral [n = 12] and posterior [n = 6]) in normal anesthetized Wistar rats. Response thresholds to electronic von Frey anesthesiometer (rigid tip) mechanical trunk stimuli applied in 3 lumbar directions (dorsal-ventral, 45° caudal, and 45° cranial) were determined before and immediately after the delivery of 3 HVLA-SM thrust durations (time control 0, 100, and 400 milliseconds). Mean changes in mechanical trunk activation thresholds were compared using a mixed model analysis of variance. RESULTS: High-velocity, low-amplitude spinal manipulation duration did not significantly alter NS lateral thalamic neurons' mechanical trunk responses to any of the 3 directions tested with the anesthesiometer. CONCLUSIONS: This study is the first to examine the effect of HVLA-SM thrust duration on NS lateral thalamic mechanical response thresholds. High-velocity, low-amplitude spinal manipulation thrust duration did not affect mechanical trunk thresholds.

Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways.

To achieve its precise neural connectivity, the developing mammalian nervous system undergoes extensive activity-dependent synapse remodelling. Recently, microglial cells have been shown to be responsible for a portion of synaptic pruning, but the remaining mechanisms remain unknown. Here we report a new role for astrocytes in actively engulfing central nervous system synapses. This process helps to mediate synapse elimination, requires the MEGF10 and MERTK phagocytic pathways, and is strongly dependent on neuronal activity. Developing mice deficient in both astrocyte pathways fail to refine their retinogeniculate connections normally and retain excess functional synapses. Finally, we show that in the adult mouse brain, astrocytes continuously engulf both excitatory and inhibitory synapses. These studies reveal a novel role for astrocytes in mediating synapse elimination in the developing and adult brain, identify MEGF10 and MERTK as critical proteins in the synapse remodelling underlying neural circuit refinement, and have important implications for understanding learning and memory as well as neurological disease processes.

Identification of the muscarinic pathway underlying cessation of sleep-related burst activity in rat thalamocortical relay neurons.

Modulation of the standing outward current (I (SO)) by muscarinic acetylcholine (ACh) receptor (MAChR) stimulation is fundamental for the state-dependent change in activity mode of thalamocortical relay (TC) neurons. Here, we probe the contribution of MAChR subtypes, G proteins, phospholipase C (PLC), and two pore domain K(+) (K(2P)) channels to this signaling cascade. By the use of spadin and A293 as specific blockers, we identify TWIK-related K(+) (TREK)-1 channel as new targets and confirm TWIK-related acid-sensitve K(+) (TASK)-1 channels as known effectors of muscarinic signaling in TC neurons. These findings were confirmed using a high affinity blocker of TASK-3 and TREK-1, namely, tetrahexylammonium chloride. It was found that the effect of muscarinic stimulation was inhibited by M(1)AChR-(pirenzepine, MT-7) and M(3)AChR-specific (4-DAMP) antagonists, phosphoinositide-specific PLCß (PI-PLC) inhibitors (U73122, ET-18-OCH(3)), but not the phosphatidylcholine-specific PLC (PC-PLC) blocker D609. By comparison, depleting guanosine-5'-triphosphate (GTP) in the intracellular milieu nearly completely abolished the effect of MAChR stimulation. The block of TASK and TREK channels was accompanied by a reduction of the muscarinic effect on I (SO). Current-clamp recordings revealed a membrane depolarization following MAChR stimulation, which was sufficient to switch TC neurons from burst to tonic firing under control conditions but not during block of M(1)AChR/M(3)AChR and in the absence of intracellular GTP. These findings point to a critical role of G proteins and PLC as well as TASK and TREK channels in the muscarinic modulation of thalamic activity modes.

Cortical modulation of the transient visual response at thalamic level: a TMS study.

The transient visual response of feline dorsal lateral geniculate nucleus (dLGN) cells was studied under control conditions and during the application of repetitive transcranial magnetic stimulation at 1 Hz (rTMS@1Hz) on the primary visual cortex (V1). The results show that rTMS@1Hz modulates the firing mode of Y cells, inducing an increase in burst spikes and a decrease in tonic firing. On the other hand, rTMS@1Hz modifies the spatiotemporal characteristics of receptive fields of X cells, inducing a delay and a decrease of the peak response, and a change of the surround/center amplitude ratio of RF profiles. These results indicate that V1 controls the activity of the visual thalamus in a different way in the X and Y pathways, and that this feedback control is consistent with functional roles associated with each cell type.

[Some structural characteristics of the ventral posterior lateral nucleus of the thalamus in men and women].

Using quantitative neurohistological indices, a structure of the ventral posterior lateral nucleus of the thalamus has been studied in 10 cases from the collection of the Institute of Brain, Russian Academy of Medical Sciences. The sample included 6 men and 4 women aged from 19 to 55 years, right-handed, who died suddenly and did not suffer neurological or mental disorders. Density of satellite gliocytes and density of neurons surrounded by satellite gliocytes were determined. Variability of these characteristics was related to sex and hemisphere differences. The index of satellite glia in 0.001 mm(3) was more variable in the right side both in men and women. The index of neurons surrounded by satellite gliocytes was more variable in the left side in men and in the right side in women. The asymmetry of neuron-glia ratio in the ventral posterior lateral nucleus of the thalamus was not marked. But there was a trend to its predominance in the left hemisphere compared to the right one both in men and women. However, the characteristics studied were more variable in men while the asymmetry was more marked in women.

Parallel but separate inputs from limbic cortices to the mammillary bodies and anterior thalamic nuclei in the rat.

The proposal that separate populations of subicular cells provide the direct hippocampal projections to the mammillary bodies and anterior thalamic nuclei was tested by placing two different fluorescent tracers in these two sites. In spite of varying the injection locations within the mammillary bodies and within the three principal anterior thalamic nuclei and the lateral dorsal thalamic nucleus, the overall pattern of results remained consistent. Neurons projecting to the thalamus were localized to the deepest cell populations within the subiculum while neurons projecting to the mammillary bodies consisted of more superficially placed pyramidal cells within the subiculum. Even when these two cell populations become more intermingled, e.g., in parts of the intermediate subiculum, almost no individual cells were found to project to both diencephalic targets. In adjacent limbic areas, i.e., the retrosplenial cortex, postsubiculum, and entorhinal cortex, populations of cells that project to the anterior thalamic nuclei and mammillary bodies were completely segregated. This segregated pattern included afferents to those nuclei comprising the head-direction system. The sole exception was a handful of double-labeled cells, mainly confined to the ventral subiculum, that were only found after pairs of injections in the anteromedial thalamic nucleus and mammillary bodies. The projections to the anterior thalamic nuclei also had a septal-temporal gradient with relatively fewer cells projecting from the ventral (temporal) subiculum. These limbic projections to the mammillary bodies and anterior thalamus comprise a circuit that is vital for memory, within which the two major components could convey parallel, independent information.

Organization and morphology of thalamocortical neurons of mouse ventral lateral thalamus.

The ventral lateral nucleus of the thalamus (VL) serves as a central integrative center for motor control, receiving inputs from the cerebellum, striatum, and cortex and projecting to the primary motor cortex. We aimed to determine the somatotopy and morphological features of the thalamocortical neurons within mouse VL. Retrograde tracing studies revealed that whisker-related VL neurons were found relatively anterior and medial to those labeled following injection of retrograde tracer into hindpaw motor areas. Simultaneous injections of fluorescent microspheres in both cortical regions did not result in double-labeled neurons in VL. Quantitative analysis of dendritic and somatic morphologies did not reveal any differences between hindpaw and whisker thalamocortical neurons within VL. The morphology of the thalamocortical neurons within mouse VL is similar to those in other mammals and suggests that mouse can be used as a model system for studying thalamocortical transformations within the motor system as well as plasticity following sensory deprivation or enrichment.

Synaptic organization of the tectorecipient zone of the rat lateral posterior nucleus.

Dorsal thalamic nuclei have been categorized as either "first-order" nuclei that gate the transfer of relatively unaltered signals from the periphery to the cortex or "higher order" nuclei that transfer signals from one cortical area to another. To classify the tectorecipient lateral posterior (LPN), we examined the synaptic organization of tracer-labeled cortical and tectal terminals and terminals labeled with antibodies against the type 1 and type 2 vesicular glutamate transporters (vGLUT1 and vGLUT2) within the caudal/lateral LPN of the rat. For this zone, we found that all tracer-labeled cortical terminals, as well as vGLUT1 antibody-labeled terminals, are small profiles with round vesicles (RS profiles) that innervate small-caliber dendrites. Tracer-labeled tecto-LPN terminals, as well as vGLUT2 antibody-labeled terminals, were medium-sized profiles with round vesicles (RM profiles). Tecto-LPN terminals were significantly larger than cortico-LPN terminals and contacted significantly larger dendrites. These results indicate that, within the tectorecipient zone of the rat LPN, cortical terminals are located distal to tectal terminals and that vGLUT1 and vGLUT2 antibodies may be used as markers for cortical and tectal terminals, respectively. Finally, comparisons of the synaptic patterns formed by tracer-labeled terminals with those of vGLUT antibody-labeled terminals suggest that individual LPN neurons receive input from multiple cortical and tectal axons. We suggest that the tectorecipient LPN constitutes a third category of thalamic nucleus ("second-order") that integrates convergent tectal and cortical inputs. This organization may function to signal the movement of novel or threatening objects moving across the visual field.

Retrograde analysis of the cerebellar projections to the posteroventral part of the ventral lateral thalamic nucleus in the macaque monkey.

The organization of cerebellothalamic projections was investigated in macaque monkeys using injections of retrograde tracers (cholera toxin B and fluorescent dextrans) in the posteroventral part of the ventrolateral thalamic nucleus (VLpv), the main source of thalamic inputs to the primary motor cortex. Injections that filled all of VLpv labeled abundant neurons that were inhomogeneously distributed among many unlabeled cells in the deep cerebellar nuclei (DCbN). Single large pressure injections made in face-, forelimb-, or hindlimb-related portions of VLpv using physiological guidance labeled numerous neurons that were broadly dispersed within a coarse somatotopographic anteroposterior (foot to face) gradient in the dentate and interposed nuclei. Small iontophoretic injections labeled fewer neurons with the same somatotopographic gradient, but strikingly, the labeled neurons in these cases were as broadly dispersed as in cases with large injections. Simultaneous injections of multiple tracers in VLpv (one tracer per somatic region with no overlap between injections) confirmed the general somatotopography but also demonstrated clearly the overlapping distributions and the close intermingling of neurons labeled with different tracers. Significantly, very few neurons (<2%) were double-labeled. This organizational pattern contrasts with the concept of a segregated "point-to-point" somatotopy and instead resembles the complex patterns that have been observed throughout the motor pathway. These data support the idea that muscle synergies are represented anatomically in the DCbN by a general somatotopography in which intermingled neurons and dispersed but selective connections provide the basis for plastic, adaptable movement coordination of different parts of the body. Indexing terms:

Organization of anterior cingulate and frontal cortical projections to the anterior and laterodorsal thalamic nuclei in the rat.

The anterior and laterodorsal thalamic nuclei provide massive projections to the anterior cingulate and frontal cortices in the rat. However, the organization of reciprocal corticothalamic projections has not yet been studied comprehensively. In the present study, we clarified the organization of anterior cingulate and frontal cortical projections to the anterior and laterodorsal thalamic nuclei, using retrograde and anterograde axonal transport methods. The anteromedial nucleus (AM) receives mainly ipsilateral projections from the prelimbic and medial orbital cortices and bilateral projections from the anterior cingulate and secondary motor cortices. The projections from the anterior cingulate cortex are organized such that the rostrocaudal axis of the AM corresponds to the rostrocaudal axis of the cortex, whereas those from the secondary motor cortex are organized such that the rostrocaudal axis of the AM corresponds to the caudorostral axis of the cortex. The ventromedial part of the anteroventral nucleus receives ipsilateral projections from the anterior cingulate cortex and bilateral projections from the secondary motor cortex, in a topographic manner similar to the projections to the AM. The ventromedial part of the laterodorsal nucleus (LD) receives ipsilateral projections from the anterior cingulate and secondary motor cortices. The projections are roughly organized such that more dorsal and ventral regions within the ventromedial LD receive projections preferentially from the anterior cingulate cortex. The difference in anterior cingulate and frontal cortical projections to the anterior and laterodorsal nuclei may suggest that each thalamic nucleus plays a different functional role in spatial memory processing.

Mapping by laser photostimulation of connections between the thalamic reticular and ventral posterior lateral nuclei in the rat.

We used laser scanning photostimulation through a focused UV laser of caged glutamate in an in vitro slice preparation through the rat's somatosensory thalamus to study topography and connectivity between the thalamic reticular nucleus and ventral posterior lateral nucleus. This enabled us to focally stimulate the soma or dendrites of reticular neurons. We were thus able to confirm and extend previous observations based mainly on neuroanatomical pathway tracing techniques: the projections from the thalamic reticular nucleus to the ventral posterior lateral nucleus have precise topography. The reticular zone, which we refer to as a "footprint," within which photostimulation evoked inhibitory postsynaptic currents (IPSCs) in relay cells, was relatively small and oval, with the long axis being parallel to the border between the thalamic reticular nucleus and ventral posterior lateral nucleus. These evoked IPSCs were large, and by using appropriate GABA antagonists, we were able to show both GABA(A) and GABA(B) components. This suggests that photostimulation strongly activated reticular neurons. Finally, we were able to activate a disynaptic relay cell-to-reticular-to- relay cell pathway by evoking IPSCs in relay cells from photostimulation of the region surrounding a recorded relay cell. This, too, suggests strong responses of relay cells, responses strong enough to evoke spiking in their postsynaptic reticular targets. The regions of photostimulation for these disynaptic responses were much larger than the above-mentioned reticular footprints, and this suggests that reticulothalamic axon arbors are less widespread than thalamoreticular arbors, that there is more convergence in thalamoreticular connections than in reticulothalamic connections, or both.

The lateral ventromedial thalamic nucleus spreads nociceptive signals from the whole body surface to layer I of the frontal cortex.

Neurons within the lateral ventromedial thalamic nucleus (VMl) convey selectively nociceptive information from all parts of the body. The present experiments were performed in rats and were designed to determine the organization of cortical projections from VMl neurons. In a first series of experiments, these cells were characterized electrophysiologically and individually labelled in a Golgi-like manner following juxtacellular electrophoresis of biotin-dextran. In a second experimental series, topical applications of the tracers fluorogold and tetramethylrhodamine-labelled dextran were placed into both the rostral-most and caudal areas of layer I of the dorsolateral frontal cortex, respectively. All VMl nociceptive neurons were fusiform and their full dendritic arborizations were bipolar, extending in the lateromedial axis. VMl cells are thus particularly well located to receive widespread nociceptive inputs via a brainstem link, viz. the medullary subnucleus reticularis dorsalis. VMl neurons driven by 'whole body' nociceptive receptive fields project to the rostral part of the layer I of the dorsolateral frontal cortex. These projections are widespread because double-labelling data showed a great number of VMl neurons labelled from both rostral and caudal dorsolateral cortices. The VMl comprises a homogeneous, organized subset of thalamic neurons that allow any signals of pain to modify cortical activity in a widespread manner, by interacting with the entire layer I of the dorsolateral neocortex.

Overlap and interdigitation of cortical and thalamic afferents to dorsocentral striatum in the rat.

Dorsocentral striatum (DCS) is an associative region necessary for directed attention in rats. DCS is defined as the main region in which axons from ipsilateral medial agranular cortex (AGm) terminate within the striatum. In this double-labeling study, we placed a green axonal tracer in area AGm and a red one in an additional brain region. We examined the spatial relationship between terminals from area AGm and other portions of the cortical-basal ganglia-thalamic-cortical network involved in directed attention and its dysfunction, hemispatial neglect, in the rat. These include lateral agranular cortex (AGl), posterior parietal cortex (PPC), ventrolateral orbital cortex (VLO), and secondary visual cortex (Oc2M). One important finding is the presence of a dense focus of labeled axons within DCS after injections in cortical area PPC or Oc2M. In these foci, axons from PPC or Oc2M extensively overlap and interdigitate with axons from cortical area AGm. Additionally, retrograde labeling of striatal neurons, along with double anterograde labeling, suggests that axons from cortical area AGm and AGl cross and possibly make contact with the dendritic processes of single medium spiny neurons. Axons from thalamic nucleus LP were observed to form a dense band dorsal to DCS which is similar to that seen following PPC injections, and a significant number of LP axons were also observed within DCS. Projections from thalamic nucleus VL are present in the dense dorsolateral AGm band that abuts the external capsule, are densest in the dorsolateral striatum, and were not observed in DCS. These results extend previous findings that DCS receives input from diverse cortical areas and thalamic nuclei which are themselves interconnected.

Thalamo-cortical projections to the posterior parietal cortex in the monkey.

Thalamo-cortical projections to the posterior parietal cortex (PPC) were investigated electrophysiologically in the monkey. Cortical field potentials evoked by the thalamic stimulation were recorded with electrodes chronically implanted on the cortical surface and at a 2.0-3.0 mm cortical depth in the PPC. The stimulation of the nucleus lateralis posterior (LP), nucleus ventralis posterior lateralis pars caudalis (VPLc), and nucleus pulvinaris lateralis (Pul.l) and medialis (Pul.m) induced surface-negative, depth-positive potentials in the PPC. The LP and VPLc projected mainly to the superior parietal lobule (SPL) and the anterior bank of the intraparietal sulcus (IPS), and the Pul.m mainly to the inferior parietal lobule (IPL) and the posterior bank of the IPS. The Pul.l had projections to all of the SPL, the IPL and both the banks. The significance of the projections is discussed in connection with motor functions.

[Psychiatric disorders and neural mechanisms underlying energy intake and expenditure: a review].

Anorexia is one of the common symptoms caused by various psychiatric disorders. Increasing evidence indicates that neuroleptics can induce weight gain, obesity, and diabetes mellitus. However, the mechanisms underlying these conditions have not been fully elucidated. In this review, we describe molecular neuroanatomic aspects of current biology of energy homeostasis that would help to address the psychiatric issues noted above, focusing on the central leptin/melanocortin system. An adipocyte-derived hormone, leptin acts on the arcuate hypothalamic nucleus (Arc) to inhibit feeding behavior and simultaneously to promote energy expenditure. Leptin activates Arc neurons producing alpha-melanocyte-stimulating hormone (alpha-MSH) and inhibits those producing agouti-related protein (AgRP). alpha-MSH is an endogenous agonist for the melanocortin-4 receptor (MC4-R) that is expressed exclusively in the central nervous system (CNS), whereas AgRP acts as a MC4-R antagonist. It is also established that MC4-R blockade produces an over-eating/obesity syndrome in rodents and humans. Thus, MC4-R-expressing neurons are downstream targets of leptin. Of interest, MC4-R-positive neurons densely populate in CNS sites critical for energy homeostasis and associated with psychiatric disorders, including the paraventricular hypothalamic nucleus and central amygdaloid nucleus. In addition, Arc alpha-MSH neurons receive serotonergic inputs from raphe neurons. Finally, an AgRP gene polymorphism has been associated with anorexia nervosa. These findings suggest that the central melanocortin system is a target for psychiatry.