How our internal state is merged with our visual perception of an impending threat to drive an adaptive behavioural response is not known. Mice respond to visual threats by either freezing or seeking shelter. Here we show that nuclei of the ventral midline thalamus (vMT), the xiphoid nucleus (Xi) and nucleus reuniens (Re), represent crucial hubs in the network controlling behavioural responses to visual threats. The Xi projects to the basolateral amygdala to promote saliency-reducing responses to threats, such as freezing, whereas the Re projects to the medial prefrontal cortex (Re→mPFC) to promote saliency-enhancing, even confrontational responses to threats, such as tail rattling. Activation of the Re→mPFC pathway also increases autonomic arousal in a manner that is rewarding. The vMT is therefore important for biasing how internal states are translated into opposing categories of behavioural responses to perceived threats. These findings may have implications for understanding disorders of arousal and adaptive decision-making, such as phobias, post-traumatic stress and addictions.
Limited functional recovery can be achieved with rehabilitation after incomplete spinal cord injury. Eliminating the function of a repulsive Wnt receptor, Ryk, by either conditional knockout in the motor cortex or monoclonal antibody infusion, resulted in increased corticospinal axon collateral branches with pre-synaptic puncta in the spinal cord and enhanced recovery of forelimb reaching and grasping function following a cervical dorsal column lesion. Using optical stimulation, we observed that motor cortical output maps underwent massive changes after injury and the hindlimb cortical areas were recruited to control the forelimb over time. Furthermore, a greater cortical area was dedicated to control the forelimb in Ryk cKO. In the absence of weekly task-specific training, recruitment of ectopic cortical areas was greatly reduced without significant functional recovery even in Ryk cKO. Our study provides evidence that maximal circuit reorganization and functional recovery can be achieved by combining molecular manipulation and task-specific training.
Studies show that limited functional recovery can be achieved by plasticity and adaptation of the remaining circuitry in partial injuries in the central nervous system, although the new circuits that arise in these contexts have not been clearly identified or characterized. We show here that synaptic contacts from dorsal root ganglions to a small number of dorsal column neurons, a caudal extension of nucleus gracilis, whose connections to the thalamus are spared in a precise cervical level 1 lesion, underwent remodeling over time. These connections support proprioceptive functional recovery in a conditioning lesion paradigm, as silencing or eliminating the remodelled circuit completely abolishes the recovered proprioceptive function of the hindlimb. Furthermore, we show that blocking repulsive Wnt signalling increases axon plasticity and synaptic connections that drive greater functional recovery.
Molecular and cellular mechanisms underlying the peripheral conditioning lesion remain unsolved. We show here that injection of a chemical demyelinating agent, ethidium bromide, into the sciatic nerve induces a similar set of regeneration-associated genes and promotes a 2.7-fold greater extent of sensory axon regeneration in the spinal cord than sciatic nerve crush. We found that more severe peripheral demyelination correlates with more severe functional and electrophysiological deficits, but more robust central regeneration. Ethidium bromide injection does not activate macrophages at the demyelinated sciatic nerve site, as observed after nerve crush, but briefly activates macrophages in the dorsal root ganglion. This study provides a new method for investigating the underlying mechanisms of the conditioning response and suggests that loss of the peripheral myelin may be a major signal to change the intrinsic growth state of adult sensory neurons and promote regeneration.
The use of sensory information to drive specific behaviors relies on circuits spanning long distances that wire up through a range of axon-target recognition events. Mechanisms assembling poly-synaptic circuits and the extent to which parallel pathways can "cross-wire" to compensate for loss of one another remain unclear and are crucial to our understanding of brain development and models of regeneration. In the visual system, specific retinal ganglion cells (RGCs) project to designated midbrain targets connected to downstream circuits driving visuomotor reflexes. Here, we deleted RGCs connecting to pupillary light reflex (PLR) midbrain targets and discovered that axon-target matching is tightly regulated. RGC axons of the eye-reflex pathway avoided vacated PLR targets. Moreover, downstream PLR circuitry is maintained; hindbrain and peripheral components retained their proper connectivity and function. These findings point to a model in which poly-synaptic circuit development reflects independent, highly stringent wiring of each parallel pathway and downstream station.
SUMMARY(1) The single inhibitor axon of one side, going to the cardiac ganglion of Panulirus in a preparation with the central nervous system removed, was stimulated a t a constant mean frequency but with different temporal fine structure. In particular, inhibitory trains with uniform intervals are compared with trains of alternately short and long intervals ("paired pulses"). Different ratios of short to long interval were used and, besides pairs, groups of up to 8 shocks. (2) Sixteen different measures of the inhibitory effect upon various aspects of the electroneurogram of the heart beat are compared. Some are more sensitive, others are more consistent. (3) Pattern sensitivity is found, that is the heart beat slows to different extents for different temporal structures. Trains of uniform intervals were generally more effective than any other pattern. Bursts of 7 or 8 are less effective than shorter bursts with the same minimum and mean interval. (4) The same burst has a different effect according to the phase of the heart cycle at which it arrives; the later the arrival the greater the effect. At the optimal phase and impulse interval, the minimum number of impulses for a just noticeable inhibitory effect (&lo%) is about 4. (5) I n some preparations aging was associated with a reversal from inhibition to acceleration and such changes were not necessarily in parallel for different stimulus patterns. (6) On present evidence it cannot be said that the pattern sensitivity is explained by the effect of conditioning shock-test shock interval on the synaptic response t o the test shock. (7) Evidence does not yet permit evaluation of the possible role of pattern sensitivity under normal conditions. The significance at present is the finding that in a nearly ideal preparation for testing, a RAO, B A B U , ISHIKO, A N D BULLOCKpostsynaptic neuron can "read," i.e., respond differently to the same mean frequency according to temporal fine structure.
Highlights 32 33 • Tbx20 plays a role in the development of non-image-forming pathways. 34 35 • Loss of Tbx20-expressing RGCs alters specific aspects of the pupil reflex arc. 36 37 • Previously unknown role for a specific subset of Tbx20-expressing RGCs in 38 modulating pupil size. 39 40 eTOC 41 Dhande et al. identify a novel genetic program that marks and is required for the 42 development of non-image-forming parallel visual pathways. Moreover, chemogenetic 43 activation of a specific retina-to-OPN pathway reveals a novel circuit element controlling 44 pupil size. These findings provide new insight into the mechanisms that establish defining 45 features of functionally specialized sensory pathways. 46 47space. We discovered that Tbx20 expression is mostly restricted to three RGC-types: M1 56 intrinsically photosensitive RGCs (ipRGCs), M2 ipRGCs and 'diving' RGCs. The axonal 57 projections of Tbx20-RGCs innervate non-image-forming brain centers including the 58 suprachiasmatic nucleus, the medial division of the posterior pretectal nucleus, and the 59 olivary pretectal nucleus (OPN), a principal station in the neural pathway for generating 60 the pupillary light reflex (PLR). Conditional deletion of Tbx20 resulted in reduced Tbx20-61 RGC axonal innervation of these targets and revealed a key role of these neurons in driving 62 specific phases of the PLR. Furthermore, chemogenetic activation uncovered a novel role 63 for a specific subset of Tbx20-RGCs in controlling pupil dilation. These data offer a new 64 understanding of the genetic and molecular mechanisms that establish specific, 65 behaviorally-relevant visual circuits. 66 67
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