Frédéric Huppé-Gourgues

Activation of the mouse primary visual cortex by medial prefrontal subregion stimulation is not mediated by cholinergic basalo-cortical projections

The medial prefrontal cortex (mPFC) exerts top-down control of primary visual cortex (V1) activity. As there is no direct neuronal projection from mPFC to V1, this functional connection may use an indirect route, i.e., via basalo-cortical cholinergic projections. The cholinergic projections to V1 originate from neurons in the horizontal limb of the diagonal band of Broca (HDB), which receive neuronal projections from the ventral part of the mPFC, composed of prelimbic (PrL) and infralimbic cortices (IL). Therefore, the objective of this study was to determine whether electrical stimulation of mice mPFC subregions activate (1) V1 neurons; and (2) HDB cholinergic neurons, suggesting that the HDB serves as a relay point in the mPFC-V1 interaction. Neuronal activation was quantified using c-Fos immunocytochemistry or thallium autometallography for each V1 layer using automated particle analysis tools and optical density measurement. Stimulation of IL and PrL induced significantly higher c-Fos expression or thallium labeling in layers II/III and V of V1 in the stimulated hemisphere only. A HDB cholinergic neuron-specific lesion by saporin administration reduced IL-induced c-Fos expression in layers II/III of V1 but not in layer V. However, there was no c-Fos expression or thallium labeling in the HDB neurons, suggesting that this area was not activated by IL stimulation. Stimulation of another mPFC subarea, the anterior cingulate cortex (AC), which is involved in attention and receives input from V1, activated neither V1 nor HDB. The present results indicate that IL and PrL, but not AC, stimulation activates V1 with the minor involvement of the HDB cholinergic projections. These results suggest a functional link between the ventral mPFC and V1, but this function is only marginally supported by HDB cholinergic neurons and may involve other brain regions.

Roles of cannabinoid receptors type 1 and 2 on the retinal function of adult mice.

PURPOSE Endocannabinoids are important modulators of synaptic transmission and plasticity throughout the central nervous system. The cannabinoid receptor type 1 (CB1R) is extensively expressed in the adult retina of rodents, while CB2R mRNA and protein expression have been only recently demonstrated in retinal tissue. The activation of cannabinoid receptors modulates neurotransmitter release from photoreceptors and could also affect bipolar cell synaptic release. However, the impact of CB1R and CB2R on the retinal function as a whole is currently unknown. METHODS In the present study, we investigated the function of cannabinoid receptors in the retina by recording electroretinographic responses (ERGs) from mice lacking either CB1 or CB2 receptors (cnr1(-/-) and cnr2(-/-), respectively). We also documented the precise distribution of CB2R by immunohistochemistry. RESULTS Our results showed that CB2R is localized in cone and rod photoreceptors, horizontal cells, some amacrine cells, and bipolar and ganglion cells. In scotopic conditions, the amplitudes of the a-wave of the ERG were increased in cnr2(-/-) mice, while they remained unchanged in cnr1(-/-) mice. The analysis of the velocity-time profile of the a-wave revealed that the increased amplitude was due to a slower deceleration rather than an increase in acceleration of the waveform. Under photopic conditions, b-wave amplitudes of cnr2(-/-) mice required more light adaptation time to reach stable values. No effects were observed in cnr1(-/-) mice. CONCLUSIONS The data indicated that CB2R is likely to be involved in shaping retinal responses to light and suggest that CB1 and CB2 receptors could have different roles in visual processing.

Boosting visual cortex function and plasticity with acetylcholine to enhance visual perception

The cholinergic system is a potent neuromodulatory system that plays critical roles in cortical plasticity, attention and learning. In this review, we propose that the cellular effects of acetylcholine (ACh) in the primary visual cortex during the processing of visual inputs might induce perceptual learning; i.e., long-term changes in visual perception. Specifically, the pairing of cholinergic activation with visual stimulation increases the signal-to-noise ratio, cue detection ability and long-term facilitation in the primary visual cortex. This cholinergic enhancement would increase the strength of thalamocortical afferents to facilitate the treatment of a novel stimulus while decreasing the cortico-cortical signaling to reduce recurrent or top-down modulation. This balance would be mediated by different cholinergic receptor subtypes that are located on both glutamatergic and GABAergic neurons of the different cortical layers. The mechanisms of cholinergic enhancement are closely linked to attentional processes, long-term potentiation (LTP) and modulation of the excitatory/inhibitory balance. Recently, it was found that boosting the cholinergic system during visual training robustly enhances sensory perception in a long-term manner. Our hypothesis is that repetitive pairing of cholinergic and sensory stimulation over a long period of time induces long-term changes in the processing of trained stimuli that might improve perceptual ability. Various non-invasive approaches to the activation of the cholinergic neurons have strong potential to improve visual perception.

D1–NMDA receptor interactions in the rat nucleus accumbens change during adolescence

Many aspects of the dopamine (DA) system mature during adolescence. For example, the DA modulation of glutamate responses in the rat prefrontal cortex (PFC) acquires adult characteristics during late adolescence. In the striatum, D1 receptors modulate NMDA responses, but whether this behaviorally important interaction matures during adolescence is not known. Here, we tested whether the D1 agonist SKF38393 affects NMDA actions on nucleus accumbens medium spiny neuron (MSN) excitability in slices from juvenile and young adult rats. NMDA dose‐dependently increased excitability in both age groups, and the D1 agonist produced a marginal increase of MSN excitability. In juvenile slices, the most common interaction was a downregulation of NMDA effects on excitability by the D1 agonist, whereas in most adult MSN, the D1 agonist increased NMDA effects on MSN excitability. These results suggest that D1–NMDA receptor interactions in the nucleus accumbens change during adolescence, a change that may result in different processing of reward functions during this critical developmental stage. Synapse, 2012.

Distribution, Morphology, and Synaptic Targets of Corticothalamic Terminals in the Cat Lateral Posterior-Pulvinar Complex that Originate from the Posteromedial Lateral Suprasylvian Cortex

The lateral posterior (LP) nucleus is a higher order thalamic nucleus that is believed to play a key role in the transmission of visual information between cortical areas. Two types of cortical terminals have been identified in higher order nuclei, large (type II) and smaller (type I), which have been proposed to drive and modulate, respectively, the response properties of thalamic cells (Sherman and Guillery [1998] Proc. Natl. Acad. Sci. U. S. A. 95:7121–7126). The aim of this study was to assess and compare the relative contribution of driver and modulator inputs to the LP nucleus that originate from the posteromedial part of the lateral suprasylvian cortex (PMLS) and area 17. To achieve this goal, the anterograde tracers biotinylated dextran amine (BDA) or Phaseolus vulgaris leucoagglutinin (PHAL) were injected into area 17 or PMLS. Results indicate that area 17 injections preferentially labelled large terminals, whereas PMLS injections preferentially labelled small terminals. A detailed analysis of PMLS terminal morphology revealed at least four categories of terminals: small type I terminals (57%), medium‐sized to large singletons (30%), large terminals in arrangements of intermediate complexity (8%), and large terminals that form arrangements resembling rosettes (5%). Ultrastructural analysis and postembedding immunocytochemical staining for γ‐aminobutyric acid (GABA) distinguished two types of labelled PMLS terminals: small profiles with round vesicles (RS profiles) that contacted mostly non‐GABAergic dendrites outside of glomeruli and large profiles with round vesicles (RL profiles) that contacted non‐GABAergic dendrites (55%) and GABAergic dendritic terminals (45%) in glomeruli. RL profiles likely include singleton, intermediate, and rosette terminals, although future studies are needed to establish definitively the relationship between light microscopic morphology and ultrastructural features. All terminals types appeared to be involved in reciprocal corticothalamocortical connections as a result of an intermingling of terminals labelled by anterograde transport and cells labelled by retrograde transport. In conclusion, our results indicate that the origin of the driver inputs reaching the LP nucleus is not restricted to the primary visual cortex and that extrastriate visual areas might also contribute to the basic organization of visual receptive fields of neurons in this higher order nucleus. J. Comp. Neurol. 497:847–863, 2006.

Effects of the intravitreal administration of dopaminergic ligands on the b-wave amplitude of the rabbit electroretinogram

In the retina of mammals, dopamine (DA) is generally released by amacrine cells and is known to alter the physiology of most retinal cells. It is well known that DA reduces the amplitude of the b-wave of the electroretinogram (ERG) in rabbit. However, the specific receptor subtypes that mediate this action have not yet been elucidated. To do this, we recorded flash ERGs before and after the intravitreal injection of D1-like DA receptor agonists (SKF38393, A77693) and antagonist (SCH23390), and of D2-like agonist (R(-)-propylnorapomorphine hydrochloride; NPA) and antagonist ((S)-(-)-sulpiride). Contralateral control eyes were injected with the vehicle only. Both D1 agonists provoked a reduction of the ERG b-wave amplitude (34.0% and 59.2% of the pre-injection level, respectively). The D2-like agonist NPA had no significant effects on ERG components. Unexpectedly, both D1- and D2-like antagonists also reduced the b-wave amplitude (28.9% and 59.8%). Overall, these data suggest that the previously described effect of DA on the rabbit ERG b-wave came from activation of D1-like receptors. On the basis of the effects observed with D2-like antagonist, a subtle contribution of D2-like presynaptic receptors cannot be ruled out.

Periadolescent changes of D2–AMPA interactions in the rat nucleus accumbens

Many aspects of dopamine (DA) systems mature during adolescence. In the nucleus accumbens, the modulation of prefrontal cortical synaptic responses by DA becomes refined during adolescence with the recruitment of a gamma‐amino butyric acid (GABA) component. As this GABA component is depolarizing, it remains to be determined whether this change affects action potential firing in nucleus accumbens neurons. Here we tested whether a D2 agonist affects AMPA‐evoked cell firing in slices containing the nucleus accumbens from juvenile (postnatal day, PD 28–34) and adult (PD > 60) rats. 2‐amino‐3‐(5‐methyl‐3‐oxo‐1,2‐oxazol‐4‐yl)propanoic acid (AMPA) (0.1–0.4 μM) depolarized nucleus accumbens neurons and increased their firing in a dose‐dependent manner. The D2 agonist quinpirole (2 μM) had different effects in juvenile vs. adult slices. In the juvenile accumbens, quinpirole enhanced AMPA (0.2 μM) effects on evoked firing in a subset of neurons while it had no effect on the rest. In the adult accumbens, the D2 agonist instead attenuated the effect of AMPA on evoked firing, an interaction that was blocked by the GABA‐A antagonist picrotoxin (50 μM). Thus, D2 receptors modulate AMPA responses in the nucleus accumbens differently in juvenile than adult rats, and the adult effect requires local GABA transmission. The incorporation of a GABA component in the modulation of information processing in the nucleus accumbens by DA during adolescence may allow for a better contrast in cortically activated ensembles. Synapse, 2012.

Impaired functional organization in the visual cortex of muscarinic receptor knock-out mice

Acetylcholine modulates maturation and neuronal activity through muscarinic and nicotinic receptors in the primary visual cortex. However, the specific contribution of different muscarinic receptor subtypes in these neuromodulatory mechanisms is not fully understood. The present study evaluates in vivo the functional organization and the properties of the visual cortex of different groups of muscarinic receptor knock-out (KO) mice. Optical imaging of intrinsic signals coupled to continuous and episodic visual stimulation paradigms was used. Retinotopic maps along elevation and azimuth were preserved among the different groups of mice. However, compared to their wild-type counterparts, the apparent visual field along elevation was larger in M2/M4-KO mice but smaller in M1-KO. There was a reduction in the estimated relative receptive field size of V1 neurons in M1/M3-KO and M1-KO mice. Spatial frequency and contrast selectivity of V1 neuronal populations were affected only in M1/M3-KO and M1-KO mice. Finally, the neuronal connectivity was altered by the absence of M2/M4 muscarinic receptors. All these effects suggest the distinct roles of different subtypes of muscarinic receptors in the intrinsic organization of V1 and a strong involvement of the muscarinic transmission in the detectability of visual stimuli.

Cholinergic depletion in nucleus accumbens impairs mesocortical dopamine activation and cognitive function in rats

In rats, selective depletion of the cholinergic interneurons in the ventral striatum (nucleus accumbens or N.Acc.) results in heightened behavioural sensitivity to amphetamine and impaired sensorimotor gating processes, suggesting a hyper-responsiveness to dopamine (DA) activity in the N.Acc. We hypothesized that local cholinergic depletion may also trigger distal functional alterations, particularly in prefrontal cortex (PFC). Adult male Sprague-Dawley rats were injected bilaterally in the N.Acc. with an immunotoxin targeting choline acetyltransferase. Two weeks later, cognitive function was assessed using the delayed alternation paradigm in the T-maze. The rats were then implanted with voltammetric recording electrodes in the ventromedial PFC to measure in vivo extracellular DA release in response to mild tail pinch stress. The PFC was also examined for density of tyrosine hydroxylase (TH)-labelled varicosities. In another cohort of control and lesioned rats, we measured post mortem tissue content of DA. Depletion of cholinergic neurons (restricted to N.Acc.) significantly impaired delayed alternation performance across delay intervals. While (basal) post mortem indices of PFC DA function were unaffected by N.Acc. lesions, in vivo mesocortical DA activation was markedly reduced; this deficit correlated significantly with cognitive impairments. TH-labelled varicosities however, were unaffected in cortical layer V relative to controls. These data suggest that selective depletion of cholinergic interneurons in N.Acc. triggers widespread functional impairments in mesocorticolimbic DA function and cognition. The possible relevance of these findings is also discussed in relation to schizophrenia, where reduced density of cholinergic neurons in ventral striatum has been reported.

Distribution and effects of the muscarinic receptor subtypes in the primary visual cortex.

Muscarinic cholinergic receptors modulate the activity and plasticity of the visual cortex. Muscarinic receptors are divided into five subtypes that are not homogeneously distributed throughout the cortical layers and cells types. This distribution results in complex action of the muscarinic receptors in the integration of visual stimuli. Selective activation of the different subtypes can either strengthen or weaken cortical connectivity (e.g., thalamocortical vs. corticocortical), i.e., it can influence the processing of certain stimuli over others. Moreover, muscarinic receptors differentially modulate some functional properties of neurons during experience-dependent activity and cognitive processes and they contribute to the fine-tuning of visual processing. These functions are involved in the mechanisms of attention, maturation and learning in the visual cortex. This minireview describes the anatomo-functional aspects of muscarinic modulation of the primary visual cortex’s (V1) microcircuitry.