Figure 1
GABA B receptor-mediated modulation of the retinogeniculate synapse. A, The effects of baclofen (2 M ) and CGP55845 (CGP) (10 M ) on the synaptic response to pairs of
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Modulatory projections from brainstem nuclei and intrinsic thalamic interneurons play a significant role in modifying sensory information as it is relayed from the thalamus to the cortex. In the lateral geniculate nucleus (LGN), neurotransmitters released from these modulatory inputs can affect the intrinsic conductances of thalamocortical relay ne...
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Context 1
... of retinal fibers while the relay neuron was held at 70 mV evoked AMPA receptor (AMPAR) EPSCs that de- pressed significantly at an interstimulus interval (ISI) of 50 msec (Chen et al., 2002). Bath application of the GABA B -receptor ag- onist baclofen reduced the synaptic strength of the first EPSC from 1 to 0.05 nA ( Fig. 1 A). This inhibition was reversed with bath application of the GABA B receptor antagonist CGP55845. ...
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... inhibition was reversed with bath application of the GABA B receptor antagonist CGP55845. The amplitudes of the first (A1) and second (A2) EPSCs and the paired-pulse ratio (ppr A2/A1) are plotted as a function of time during exposure to these neuromodulators ( Fig. 1 A, left). An overlay of the average currents elicited in control conditions and in the presence of baclofen and CGP55845 shows that in addition to its effect on synaptic strength, baclofen reduced the extent of synaptic depression ( Fig. 1 A, top right). ...
Context 3
... amplitudes of the first (A1) and second (A2) EPSCs and the paired-pulse ratio (ppr A2/A1) are plotted as a function of time during exposure to these neuromodulators ( Fig. 1 A, left). An overlay of the average currents elicited in control conditions and in the presence of baclofen and CGP55845 shows that in addition to its effect on synaptic strength, baclofen reduced the extent of synaptic depression ( Fig. 1 A, top right). This is emphasized in Figure 1 A (bottom right), in which EPSCs in control conditions and in the presence of baclofen are normalized to the amplitude of the first EPSC to compare the relative strength of the second EPSC. ...
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... overlay of the average currents elicited in control conditions and in the presence of baclofen and CGP55845 shows that in addition to its effect on synaptic strength, baclofen reduced the extent of synaptic depression ( Fig. 1 A, top right). This is emphasized in Figure 1 A (bottom right), in which EPSCs in control conditions and in the presence of baclofen are normalized to the amplitude of the first EPSC to compare the relative strength of the second EPSC. The effect of baclofen was dose dependent, with 200 nM, 2 M, 10 M, and 20 M baclofen inhibiting EPSC amplitude to 54.1 5.8% (n 4), 4.1 1.4% (n 7), 6.1 1.2% (n 4), and 6.4 1.9% (n 4) of control, respectively. ...
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... address the possibility that a baseline level of tonic inhibi- tion via GABA B receptors is present at the retinogeniculate syn- apse, we studied the effects of antagonizing GABA B receptors. Bath application of CGP55845 alone did not alter the response to pairs of stimuli ( Fig. 1 B). On average, the EPSC amplitude in CGP55845 was 98.5 2.6% of control (n 4). ...
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... Presynaptic modulation of the first central synapse is widespread in sensory systems (Trussell, 2002;Chen and Regehr, 2003;Comitato and Bardoni, 2021). In the MOB, GABA B and dopamine D2 receptors have been described to balance synaptic transmission at olfactory sensory neuron (OSN) terminals (McGann, 2013). ...
Vomeronasal sensory neurons (VSNs) recognize pheromonal and kairomonal semiochemicals in the lumen of the vomeronasal organ. VSNs send their axons along the vomeronasal nerve (VN) into multiple glomeruli of the accessory olfactory bulb (AOB) and form glutamatergic synapses with apical dendrites of mitral cells, the projection neurons of the AOB. Juxtaglomerular interneurons release the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Besides ionotropic GABA receptors, the metabotropic GABAB receptor has been shown to modulate synaptic transmission in the main olfactory system. Here we show that GABAB receptors are expressed in the AOB and are primarily located at VN terminals. Electrical stimulation of the VN provokes calcium elevations in VSN nerve terminals, and activation of GABAB receptors by the agonist baclofen abolishes calcium influx in AOB slice preparations. Patch clamp recordings reveal that synaptic transmission from the VN to mitral cells can be completely suppressed by activation of GABAB receptors. A potent GABAB receptor antagonist, CGP 52432, reversed the baclofen-induced effects. These results indicate that modulation of VSNs via activation of GABAB receptors affects calcium influx and glutamate release at presynaptic terminals and likely balances synaptic transmission at the first synapse of the accessory olfactory system.
... While the core region of the dLGN might be more 'relay'-type, more neurons within the shell are selective for motion direction, stimulus orientation and changes in stimulus contrast (Marshel et al., 2012;Piscopo et al., 2013;. It is still unclear how RGC inputs shape the thalamocortical neurons' receptive fields, but converging inputs from different RGC types and presynaptic modulation challenge the classical view of these neurons as 'relays' (Chen and Regehr, 2000;Chen et al., 2002;Chen and Regehr, 2003;Jaubert-Miazza et al., 2005;Acuna-Goycolea et al., 2008;Seabrook et al., 2013;Morgan et al., 2016;Rompani et al., 2017;, corroborated by the existence of spatially-aligned, binocularly innervated dLGN neurons (Sanderson et al., 1971;Zeater et al., 2015;Howarth et al., 2014;Rompani et al., 2017). ...
Animals can react differently to similar sensory information depending on behavioural circumstances and previous experience. This flexibility is thought to depend on neural inhibition, through suppression of inappropriate and disinhibition of appropriate actions. In this thesis, I identified the ventral lateral geniculate nucleus (vLGN), an inhibitory prethalamic area, as a critical node for the control of visually evoked defensive responses in mice. First, I characterised the structural and functional organisation of the vLGN. Then, taking advantage of a well-characterised model for instinctive behavioural decisions – escape from imminent threat – I showed that GABAergic projections from vLGN to the medial superior colliculus (mSC), a known hub for threat-evoked defensive behaviours, convey information about previous experience of threat and assessment of risk in the environment. Activity in these projections was reduced when mice had experienced a threatening stimulus, while it was elevated after mice learned that stimuli did not pose any danger. Consistently, the chemogenetic suppression of vLGN activity increased risk-avoidance behaviour. The optogenetic activation of vLGN abolished escape responses to imminent visual threats, while suppressing vLGN activity increased the escape probability, demonstrating that vLGN exerts strong, bidirectional control over escape responses. Moreover, electrophysiological mSC recordings in vivo during optogenetic stimulation of vLGN, revealed that vLGN specifically suppresses the activity of visually responsive but not auditory-responsive neurons in the mSC. The optogenetic manipulation of GABAergic projections from vLGN to mSC more strongly influenced escape responses to visual than to auditory threats, suggesting a specificity of this pathway for visually guided behaviours. Together, these results indicate that vLGN flexibly controls the threshold for instinctive responses to imminent visual threat, depending on the animal’s prior experience and its anticipation of danger in the environment. These findings significantly strengthen the circuit-level understanding of flexible behaviour, and how different types of information are integrated to inform decisions.
... Specifically, optimized coding can be achieved by ensuring that the neural tuning curve matches current stimulus statistics in order to maximize information transmission [17][18][19][20][21][22][23][24][25][26] (see 12 for review). A prominent form of adaptation which has been observed across systems and species is contrast gain control, by which the neural sensitivity decreases as a function of increasing stimulus amplitude such that the neural firing rate remains within the dynamic range in order to optimize coding [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] . However, the prevailing view is that the functional advantages of such adaptation occur at the expense of increased coding ambiguity 23,32,33 . ...
... Interestingly, response gain was independent of frequency for large ramp stimulus amplitudes, which is similar to what is observed under naturalistic stimulation (compare yellow and red curves in Fig. 5A). Notably, the observed decrease in gain with increasing amplitude is a hallmark of contrast gain control adaptation which constitutes, by definition, a nonlinearity [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] . Thus, we hypothesize that gain control adaptation accounts for reduced coding ambiguity during naturalistic stimulation in vestibular thalamocortical neurons. ...
... Contrast gain control could also be due to synaptic depression at VN-VPL synapses. While such synaptic depression has been observed at equivalent synapses other areas of the thalamus (e.g., retina-LGN) 30,31 , it remains unknown if VN-VPL synapses display comparable depression. Further studies are needed to uncover the nature of the mechanism(s) leading to the observed contrast gain control adaptation in vestibular thalamocortical neurons. ...
Sensory systems must continuously adapt to optimally encode stimuli encountered within the natural environment. The prevailing view is that such optimal coding comes at the cost of increased ambiguity, yet to date, prior studies have focused on artificial stimuli. Accordingly, here we investigated whether such a trade-off between optimality and ambiguity exists in the encoding of natural stimuli in the vestibular system. We recorded vestibular nuclei and their target vestibular thalamocortical neurons during naturalistic and artificial self-motion stimulation. Surprisingly, we found no trade-off between optimality and ambiguity. Using computational methods, we demonstrate that thalamocortical neural adaptation in the form of contrast gain control actually reduces coding ambiguity without compromising the optimality of coding under naturalistic but not artificial stimulation. Thus, taken together, our results challenge the common wisdom that adaptation leads to ambiguity and instead suggest an essential role in underlying unambiguous optimized encoding of natural stimuli. Sensory adaptation is widely considered to involve a trade-off between optimality and ambiguity. Here, the authors explored sensory adaptation to both naturalistic and artificial stimuli and found that, owing to contrast gain control, there is unambiguous optimized encoding of naturalistic stimuli.
... These differences could originate from different subtypes of RGCs that innervate the dLGN and SC (Ellis et al., 2016), but they may also have other origins. Indeed, other studies have shown that local presynaptic modulation also influences the effects of arousal on the activity of retinal axonal boutons (Chen and Regehr, 2003;Lam and Sherman, 2013;Seeburg et al., 2004;Yang et al., 2014). Since RGCs project onto numerous brain targets to transfer the visual information (Martersteck et al., 2017;Morin and Studholme, 2014), we hypothesize that properties of arousal modulation that contribute to all the targets would take place at the retina, while modulations that serve a specific target would take place locally. ...
The mammalian retina is considered an autonomous circuit, yet work dating back to Ramon y Cajal indicates that it receives inputs from the brain. How such inputs affect retinal processing has remained unknown. We identified brain-to-retina projections of histaminergic neurons from the mouse hypothalamus, which densely innervated the dorsal retina. Histamine application, or chemogenetic activation of histaminergic axons, altered spontaneous and light-evoked activity of various retinal ganglion cells (RGCs), including direction-selective RGCs. These cells exhibited broader directional tuning and gained responses to high motion velocities. Such changes could improve vision when objects move fast across the visual field (e.g. while running), which fits with the known increased activity of histaminergic neurons during arousal. In humans, an antihistamine drug non-uniformly modulated visual sensitivity across the visual field, indicating an evolutionary conserved function of the histaminergic system. Our findings expose a previously unappreciated role for brain-to-retina projections in modulating retinal function.
... Third, pupil-linked modulations have also been observed in retinal input to the dLGN (Liang et al., 2020), which might be mediated by pre-synaptic modulation of the retinogeniculate synapse by serotonin (5-HT; Chen & Regehr, 2003). While thalamic relay cells are themselves generally depolarized by 5-HT (Varela & Sherman, 2009), which is consistent with our findings given that activation of the dorsal raphe is linked with pupil dilation (Cazettes et al., 2021), the dominant pre-synaptic effect of 5-HT is suppression (Chen & Regehr, 2003), consistent with the dilationrelated suppression reported by Liang et al. (2020). ...
... Third, pupil-linked modulations have also been observed in retinal input to the dLGN (Liang et al., 2020), which might be mediated by pre-synaptic modulation of the retinogeniculate synapse by serotonin (5-HT; Chen & Regehr, 2003). While thalamic relay cells are themselves generally depolarized by 5-HT (Varela & Sherman, 2009), which is consistent with our findings given that activation of the dorsal raphe is linked with pupil dilation (Cazettes et al., 2021), the dominant pre-synaptic effect of 5-HT is suppression (Chen & Regehr, 2003), consistent with the dilationrelated suppression reported by Liang et al. (2020). Therefore, how these modulations of retinal input relate to our 12 . ...
The way in which sensory systems encode information, even at early processing stages, is modulated according to the internal state of the animal. Internal states, such as arousal, are often characterized by relating neural variables to a single “level” of arousal, defined using a behavioral variable such as locomotion or pupil size. Here, we extend the notion of arousal-related modulation by showing that multifaceted aspects of pupil size dynamics can predict changes in neural activity. Specifically, we show that the phases of pupil size fluctuations occurring over multiple timescales modulate firing mode in the dorsal lateral geniculate nucleus (dLGN) of mice. Increased firing rates, driven by a preponderance of tonic spiking, occurred during pupil dilations, while burst spikes preferentially occurred during contractions. We further find that these activity modulations could not be explained solely by pupil size per se, or by transitions between overt locomotion and quiescence, and extend to periods of patterned stimulus viewing. We conclude that dLGN spiking activity is modulated by pupil-indexed arousal processes on various timescales, with implications for the determination of arousal-related cortical rhythms, and for the transfer
of sensory information to the cortex.
... Because PG cells also receive top-down centrifugal inputs, transmitter release from OSNs is subject to both local and cortical influence and neuromodulation [18,19]. This strategy of modulating sensory inputs into the brain via presynaptic GABA B receptors and local inhibitory neurons is widely adapted by other sensory systems (e.g., visual and auditory) as well [20,21]. ...
... We confirmed that light-evoked currents in the non-M72 ET cells were completely blocked by bicuculline, a GABA A receptor antagonist ( Figure 7B, bottom trace). Compared to 65% non-M72 ET cells (13 out of 20) adjacent to the control M72 glomeruli (unstimulated in the FC mice; n = 7) that showed lateral inhibition, only 20.7% (6 out of 29) ET cells adjacent to the conditioned M72 glomeruli from the same mice did ( Figure 7C; p = 0.003, c 2 test). These results suggest that fear conditioning induces multiple changes in the OB circuit to modulate how the brain processes the CS. ...
... What we have learned from the olfactory pathway may also apply to other sensory modalities as well. Presynaptic GABA B receptors and local inhibitory neurons are known to modulate visual and auditory glutamatergic inputs at their first synapses in the brain [20,21]. Fear learning based on visual or auditory cues may increase the release probability of the neurons that respond to the CS via downregulation of presynaptic GABA B receptor expression. ...
Predicting danger from previously associated sensory stimuli is essential for survival. Contributions from altered peripheral sensory inputs are implicated in this process, but the underlying mechanisms remain elusive. Here, we use the mammalian olfactory system to investigate such mechanisms. Primary olfactory sensory neurons (OSNs) project their axons directly to the olfactory bulb (OB) glomeruli, where their synaptic release is subject to local and cortical influence and neuromodulation. Pairing optogenetic activation of a single glomerulus with foot shock in mice induces freezing to light stimulation alone during fear retrieval. This is accompanied by an increase in OSN release probability and a reduction in GABAB receptor expression in the conditioned glomerulus. Furthermore, freezing time is positively correlated with the release probability of OSNs in fear-conditioned mice. These results suggest that aversive learning increases peripheral olfactory inputs at the first synapse, which may contribute to the behavioral outcome.
... Inputs to first-order sensory thalamus are often divided into feedforward ''driver'' and feedback ''modulator'' pathways (Sherman, 2016). Driver inputs stemming from ascending sensory pathways are strong but exhibit short-term depression (Castro-Alamancos, 2002;Chen and Regehr, 2003). In contrast, modulator inputs arising from layer 6 (L6) cortico-thalamic (CT) neurons are weak but show marked facilitation (Alexander et al., 2006;Cruikshank et al., 2010;Reichova and Sherman, 2004). ...
Reciprocal interactions between the prefrontal cortex (PFC) and thalamus play a critical role in cognition, but the underlying circuits remain poorly understood. Here we use optogenetics to dissect the specificity and dynamics of cortico-thalamo-cortical networks in the mouse brain. We find that cortico-thalamic (CT) neurons in prelimbic PFC project to both mediodorsal (MD) and ventromedial (VM) thalamus, where layer 5 and 6 inputs activate thalamo-cortical (TC) neurons with distinct temporal profiles. We show that TC neurons in MD and VM in turn make distinct connections in PFC, with MD preferentially and strongly activating layer 2/3 cortico-cortical (CC) neurons. Finally, we assess local connections from superficial CC to deep CT neurons, which link thalamo-cortical and cortico-thalamic networks within the PFC. Together our findings indicate that PFC strongly drives neurons in the thalamus, whereas MD and VM indirectly influence reciprocally connected neurons in the PFC, providing a mechanistic understanding of these circuits.
... R elay neurons of the dLGN transform input from the retina so that spikes with high visual information content are preferentially transmitted to the cortex 1 . Spike timing of RGCs is very important for spike transmission with a sharp increase in the transmission rate for spike frequencies of more than 30 Hz 2 suggesting that synaptic short-term plasticity plays a crucial role for input integration [3][4][5] . Retinogeniculate synapses display a pronounced short-term depression that arises partly from a high release probability 6 . ...
Relay neurons in the dorsal lateral geniculate nucleus (dLGN) receive excitatory inputs from retinal ganglion cells (RGCs). Retinogeniculate synapses are characterized by a prominent short-term depression of AMPA receptor (AMPAR)-mediated currents, but the underlying mechanisms and its function for visual integration are not known. Here we identify CKAMP44 as a crucial auxiliary subunit of AMPARs in dLGN relay neurons, where it increases AMPAR-mediated current amplitudes and modulates gating of AMPARs. Importantly, CKAMP44 is responsible for the distinctive short-term depression in retinogeniculate synapses by reducing the rate of recovery from desensitization of AMPARs. Genetic deletion of CKAMP44 strongly reduces synaptic short-term depression, which leads to increased spike probability of relay neurons when activated with high-frequency inputs from retinogeniculate synapses. Finally, in vivo recordings reveal augmented ON- and OFF-responses of dLGN neurons in CKAMP44 knockout (CKAMP44-/-) mice, demonstrating the importance of CKAMP44 for modulating synaptic short-term depression and visual input integration.
... Retinogeniculate transmission is known to be modulated presynaptically by a number of neurotransmitter receptors, including GABA B , serotonin 5HT 1B (Chen & Regehr, 2003;Seeburg et al., 2004), as well as adenosine A1 (Yang et al., 2014) and metabotropic glutamate receptors (Hauser et al., 2013;Lam & Sherman, 2013). Activation of the GABA B or 5-HT 1B receptors strongly depresses neurotransmitter release and relieves short-term depression by decreasing the entry of calcium into the presynaptic terminal (see Fig. 2B; Chen & Regehr, 2003;Seeburg et al., 2004). ...
... Retinogeniculate transmission is known to be modulated presynaptically by a number of neurotransmitter receptors, including GABA B , serotonin 5HT 1B (Chen & Regehr, 2003;Seeburg et al., 2004), as well as adenosine A1 (Yang et al., 2014) and metabotropic glutamate receptors (Hauser et al., 2013;Lam & Sherman, 2013). Activation of the GABA B or 5-HT 1B receptors strongly depresses neurotransmitter release and relieves short-term depression by decreasing the entry of calcium into the presynaptic terminal (see Fig. 2B; Chen & Regehr, 2003;Seeburg et al., 2004). While these modulators decrease the strength of the retinogeniculate EPSC, they also alter the pattern of action potentials transmitted from the pre-to post-synaptic neuron. ...
The thalamocortical (TC) relay neuron of the dorsoLateral Geniculate Nucleus (dLGN) has borne its imprecise label for many decades in spite of strong evidence that its role in visual processing transcends the implied simplicity of the term “relay”. The retinogeniculate synapse is the site of communication between a retinal ganglion cell and a TC neuron of the dLGN. Activation of retinal fibers in the optic tract causes reliable, rapid, and robust postsynaptic potentials that drive postsynaptics spikes in a TC neuron. Cortical and subcortical modulatory systems have been known for decades to regulate retinogeniculate transmission. The dynamic properties that the retinogeniculate synapse itself exhibits during and after developmental refinement further enrich the role of the dLGN in the transmission of the retinal signal. Here we consider the structural and functional substrates for retinogeniculate synaptic transmission and plasticity, and reflect on how the complexity of the retinogeniculate synapse imparts a novel dynamic and influential capacity to subcortical processing of visual information.
... This releases inhibition on peripheral inputs. Simultaneously, surrounding cortical areas increase their activity which inhibits inputs from position 2. Notice that the red line from relay cell represents presynaptic inhibition exerted by the cortical cell over the retino-thalamic synapse through metabotropic Glu receptors (Lam and Sherman 2013 space (position 1) through corticofugal axons operating via metabotropic receptors (Lam and Sherman 2013) and, simultaneously, blocks afferents from position 2 due to presynaptic inhibition mediated by GABAergic interneurons (Chen and Regehr 2003). ...
In awake monkeys, we used repetitive transcranial magnetic stimulation (rTMS) to focally inactivate visual cortex while measuring the responsiveness of parvocellular lateral geniculate nucleus (LGN) neurons. Effects were noted in 64/75 neurons, and could be divided into 2 main groups: (1) for 39 neurons, visual responsiveness decreased and visual latency increased without apparent shift in receptive field (RF) position and (2) a second group (n = 25, 33% of the recorded cells) whose excitability was not compromised, but whose RF position shifted an average of 4.5°. This change is related to the retinotopic correspondence observed between the recorded thalamic area and the affected cortical zone. The effect of inactivation for this group of neurons was compatible with silencing the original retinal drive and unmasking a second latent retinal drive onto the studied neuron. These results indicate novel and remarkable dynamics in thalamocortical circuitry that force us to reassess constraints on retinogeniculate transmission.
