Dexamphetamine increased speech and visual unimodal illusions in healthy participants without affecting temporal binding window.

OBJECTIVE: Stimuli received beyond a very short timeframe, known as temporal binding windows (TBWs), are perceived as separate events. In previous audio-visual multisensory integration (McGurk effect) studies, widening of TBWs has been observed in people with schizophrenia. The present study aimed to determine if dexamphetamine could increase TBWs in unimodal auditory and unimodal visual illusions that may have some validity as experimental models for auditory and visual hallucinations in psychotic disorders. METHODS: A double-blind, placebo-controlled, counter-balanced crossover design with permuted block randomisation for drug order was followed. Dexamphetamine (0.45 mg/kg, PO, q.d.) was administered to healthy participants. Phantom word illusion (speech illusion) and visual-induced flash illusion/VIFI (visual illusion) tests were measured to determine if TBWs were altered as a function of delay between stimuli presentations. Word emotional content for phantom word illusions was also analysed. RESULTS: Dexamphetamine significantly increased the total number of phantom words/speech illusions (p < 0.01) for pooled 220-1100 ms ISIs in kernel density estimation and the number of positive valence words heard (beta = 2.20, 95% CI [1.86, 2.55], t = 12.46, p < 0.001) with a large effect size (std. beta = 1.05, 95% CI [0.89, 1.22]) relative to placebo without affecting the TBWs. For the VIFI test, kernel density estimation for pooled 0-801 ms ISIs showed a significant difference (p < 0.01) in the data distributions of number of target flash (es) perceived by participants after receiving dexamphetamine as compared with placebo. CONCLUSIONS: Overall, healthy participants who were administered dexamphetamine (0.45 mg/kg, PO, q.d.) experienced increases in auditory and visual illusions in both phantom word illusion and VIFI tests without affecting their TBWs.

Development of a novel rodent rapid serial visual presentation task reveals dissociable effects of stimulant versus nonstimulant treatments on attentional processes.

The rapid serial visual presentation (RSVP) task and continuous performance tasks (CPT) are used to assess attentional impairments in patients with psychiatric and neurological conditions. This study developed a novel touchscreen task for rats based on the structure of a human RSVP task and used pharmacological manipulations to investigate their effects on different performance measures. Normal animals were trained to respond to a target image and withhold responding to distractor images presented within a continuous sequence. In a second version of the task, a false-alarm image was included, so performance could be assessed relative to two types of nontarget distractors. The effects of acute administration of stimulant and nonstimulant treatments for ADHD (amphetamine and atomoxetine) were tested in both tasks. Methylphenidate, ketamine, and nicotine were tested in the first task only. Amphetamine made animals more impulsive and decreased overall accuracy but increased accuracy when the target was presented early in the image sequence. Atomoxetine improved accuracy overall with a specific reduction in false-alarm responses and a shift in the attentional curve reflecting improved accuracy for targets later in the image sequence. However, atomoxetine also slowed responding and increased omissions. Ketamine, nicotine, and methylphenidate had no specific effects at the doses tested. These results suggest that stimulant versus nonstimulant treatments have different effects on attention and impulsive behaviour in this rat version of an RSVP task. These results also suggest that RSVP-like tasks have the potential to be used to study attention in rodents.

Impaired P100 among regular cannabis users in response to magnocellular biased visual stimuli.

Regular cannabis using causes vision impairment by affecting human retinal neurotransmission. However, studies less considered its impact on the subsequent visual cortical processing, key feature for the integration of the visual signal in brain. We aimed at investigating this purpose in regular cannabis users using spatial frequencies and temporal frequencies filtered visual stimuli. We recruited 45 regular cannabis users and 25 age-matched controls. We recorded visual evoked potentials during the projection of low spatial frequency (0.5 cycles/degree) or high spatial frequency gratings (15 cycles/degree), which were presented statically (0 Hz) or dynamically (8 Hz). We analyzed the amplitude, latency, and area under the curve of both P100 and N170, best EEG markers for early visual processing. Data were compared between groups by repeated measures ANCOVA. Results showed a significant decrease in P100 amplitude among regular cannabis users in low spatial frequency (F(1,67) = 4.43; p = 0.04) and in dynamic condition (F(1,67) = 4.35; p = 0.04). Analysis also reported a decrease in P100 area under the curve in regular cannabis users to low spatial frequency (F(1,67) = 4.31; p = 0.04) and in dynamic condition (F(1,67) = 7.65; p < 0.01). No effect was found on P100 latency, N170 amplitude, latency, or area under the curve. We found alteration of P100 responses to low spatial frequency and dynamic stimuli in regular cannabis users. This result could be interpreted as a preferential magnocellular impairment where such deficit could be linked to glutamatergic dysfunction. As mentioned in the literature, visual and electrophysiological anomalies in schizophrenia are related to a magnocellular dysfunction. Further studies are needed to clarify electrophysiological deficits in both populations. CLINICAL TRIALS REGISTRATION: Electrophysiological Study of the Functioning of Magnocellular Visual Pathway in Regular Cannabis Users (CAUSA MAP). [NCT02864680; ID 2013-A00097-38]. https://clinicaltrials.gov/ct2/show/NCT02864680?cond=Cannabis&cntry=FR&draw=2&rank=1.

Chronic bisphenol A exposure triggers visual perception dysfunction through impoverished neuronal coding ability in the primary visual cortex.

Contrast perception is a fundamental visual ability that allows us to distinguish objects from the background. However, whether it is perturbed by chronic exposure to environmental xenoestrogen, bisphenol A (BPA), is still elusive. Here, we used adult cats to explore BPA-induced changes in contrast sensitivity (CS) and its underlying neuronal coding mechanism. Behavioral results showed that 14 days of BPA exposure (0.4 mg/kg/day) was sufficient to induce CS declines at the tested spatial frequencies (0.05-2 cycles/deg) in all four cats. Furthermore, based on multi-channel electrophysiological recording and interneuronal correlation analysis, we found that the BPA-exposed cats exhibited an obvious up-regulation in noise correlation in the primary visual cortex (area 17, A17), thus providing a population neuronal coding basis for their perceptual dysfunction. Moreover, single neuron responses in A17 of BPA-exposed cats revealed a slight but marked decrease in CS compared to that of control cats. Additionally, these neuronal responses presented an overt decrease in signal-to-noise ratio, accompanied by increased trial-to-trial response variability (i.e., noise). To some extent, these neuron population and unit dysfunctions in A17 of BPA-exposed cats were attributable to decreased response activity of fast-spiking neurons. Together, our findings demonstrate that chronic BPA exposure restricts contrast perception, in response to impoverished neuronal coding ability in A17.

Cannabis use impacts pre-stimulus neural activity in the visual cortices of people with HIV.

People with HIV (PWH) use cannabis at a higher rate than the general population, but the influence on neural activity is not well characterized. Cannabis use among PWH may have a beneficial effect, as neuroinflammation is known to be a critical problem in PWH and cannabis use has been associated with a reduction in proinflammatory markers. Thus, it is important to understand the net impact of cannabis use on brain and cognitive function in PWH. In this study, we collected magnetoencephalographic (MEG) brain imaging data on 81 participants split across four demographically matched groups (i.e., PWH using cannabis, controls using cannabis, non-using PWH, and non-using controls). Participants completed a visuospatial processing task during MEG. Time-frequency resolved voxel time series were extracted to identify the dynamics of oscillatory and pre-stimulus baseline neural activity. Our results indicated strong theta (4-8 Hz), alpha (10-16 Hz), and gamma (62-72 Hz) visual oscillations in parietal-occipital brain regions across all participants. PWH exhibited significant behavioral deficits in visuospatial processing, as well as reduced theta oscillations and elevated pre-stimulus gamma activity in visual cortices, all of which replicate prior work. Strikingly, chronic cannabis use was associated with a significant reduction in pre-stimulus gamma activity in the visual cortices, such that PWH no longer statistically differed from controls. These results provide initial evidence that cannabis use may normalize some neural aberrations in PWH. This study fills an important gap in understanding the impact of cannabis use on brain and cognitive function in PWH.

Cannabinoids Regulate Sensory Processing in Early Olfactory and Visual Neural Circuits.

Our sensory systems such as the olfactory and visual systems are the target of neuromodulatory regulation. This neuromodulation starts at the level of sensory receptors and extends into cortical processing. A relatively new group of neuromodulators includes cannabinoids. These form a group of chemical substances that are found in the cannabis plant. Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the main cannabinoids. THC acts in the brain and nervous system like the chemical substances that our body produces, the endogenous cannabinoids or endocannabinoids, also nicknamed the brain's own cannabis. While the function of the endocannabinoid system is understood fairly well in limbic structures such as the hippocampus and the amygdala, this signaling system is less well understood in the olfactory pathway and the visual system. Here, we describe and compare endocannabinoids as signaling molecules in the early processing centers of the olfactory and visual system, the olfactory bulb, and the retina, and the relevance of the endocannabinoid system for synaptic plasticity.

Acute alcohol intoxication modulates the temporal dynamics of resting electroencephalography networks.

This study aimed to provide a currently missing link between general intoxication-induced changes in overall brain activity and the multiple cognitive control deficits typically observed during acute alcohol intoxication. For that purpose, we analyzed the effects of acute alcohol intoxication (1.1‰) on the four archetypal electroencephalography (EEG) resting networks (i.e., microstates A-D) and their temporal dynamics (e.g., coverage and transitions from one microstate to another), as well as on self-reported resting-state cognition in n = 22 healthy young males using a counterbalanced within-subject design. Our microstate analyses indicated that alcohol increased the coverage of the visual processing-related microstate B at the expense of the autonomic processing-related microstate C. Add-on exploratory analyses revealed that alcohol increased transitions from microstate C to microstate B and decreased bidirectional transitions between microstate C and the attention-related microstate D. In line with the observed alcohol-induced decrease of the autonomic processing-related microstate C, participants reported decreases of their somatic awareness during intoxication, which were positively associated with more transitions from microstate C to microstate B. In sum, the observed effects provide mechanistic insights into how alcohol might hamper cognitive processing by generally prioritizing the bottom-up processing of visual stimuli over top-down internal information processing. The fact that this was found during the resting state further proves that alcohol-induced changes in brain activity are continuously present and do not only emerge during demanding situations or tasks.

Hidden talents: Poly (I:C)-induced maternal immune activation improves mouse visual discrimination performance and reversal learning in a sex-dependent manner.

While there is a strong focus on the negative consequences of maternal immune activation (MIA) on developing brains, very little attention is directed towards potential advantages of early life challenges. In this study, we utilized a polyinosine-polycytidylic acid (poly(I:C)) MIA model to test visual pairwise discrimination (PD) and reversal learning (RL) in mice using touchscreen technology. Significant sex differences emerged in that MIA reduced the latency for males to make a correct choice in the PD task while females reached criterion sooner, made fewer errors, and utilized fewer correction trials in RL compared to saline controls. These surprising improvements were accompanied by the sex-specific upregulation of several genes critical to cognitive functioning, indicative of compensatory plasticity in response to MIA. In contrast, when exposed to a 'two-hit' stress model (MIA + loss of the social component of environmental enrichment [EE]), mice did not display anhedonia but required an increased number of PD and RL correction trials. These animals also had significant reductions of CamK2a mRNA in the prefrontal cortex. Appropriate functioning of synaptic plasticity, via mediators such as this protein kinase and others, are critical for behavioral flexibility. Although EE has been implicated in, delaying the appearance of symptoms associated with certain brain disorders, these findings are in line with evidence that it also makes individuals more vulnerable to its loss. Overall, with the right 'dose', early life stress exposure can confer at least some functional advantages, which are lost when the number or magnitude of these exposures become too great.

Oxytocin facilitates socially directed attention.

Socially directed gaze following is an important component of social interaction and communication, allowing us to attend mutually with others to objects or people so that we can share their experience and also learn from them. This type of joint social attention is impaired in disorders such as autism. Previous research has demonstrated that the neuropeptide oxytocin can facilitate attention toward social cues, although to date no study in humans has investigated its influence on socially directed gaze or on associations of the latter with autistic and empathic traits. In a within-subject, randomized, placebo-controlled trial we used eye-tracking to investigate the effects of intranasal oxytocin (24 IU) on socially directed gaze toward one of two objects in 40 adult male subjects. Subjects viewed videos of an actor and actress directing their gaze toward one of two objects by either moving only their eyes, moving both their eyes and head, or moving their eyes and head and pointing with a finger. Results showed that OXT increased the proportion of time subjects viewed the object the actor or actress were looking/pointing at across all three conditions, although unexpectedly we found no associations with trait autism or empathy under either placebo or OXT treatments. These findings demonstrate that OXT can facilitate socially directed gaze following to promote mutual attention toward objects which may be potentially beneficial therapeutically in disorders with impaired social communication and interaction.

State-Dependent Regulation of Cortical Processing Speed via Gain Modulation.

To thrive in dynamic environments, animals must be capable of rapidly and flexibly adapting behavioral responses to a changing context and internal state. Examples of behavioral flexibility include faster stimulus responses when attentive and slower responses when distracted. Contextual or state-dependent modulations may occur early in the cortical hierarchy and may be implemented via top-down projections from corticocortical or neuromodulatory pathways. However, the computational mechanisms mediating the effects of such projections are not known. Here, we introduce a theoretical framework to classify the effects of cell type-specific top-down perturbations on the information processing speed of cortical circuits. Our theory demonstrates that perturbation effects on stimulus processing can be predicted by intrinsic gain modulation, which controls the timescale of the circuit dynamics. Our theory leads to counterintuitive effects, such as improved performance with increased input variance. We tested the model predictions using large-scale electrophysiological recordings from the visual hierarchy in freely running mice, where we found that a decrease in single-cell intrinsic gain during locomotion led to an acceleration of visual processing. Our results establish a novel theory of cell type-specific perturbations, applicable to top-down modulation as well as optogenetic and pharmacological manipulations. Our theory links connectivity, dynamics, and information processing via gain modulation.SIGNIFICANCE STATEMENT To thrive in dynamic environments, animals adapt their behavior to changing circumstances and different internal states. Examples of behavioral flexibility include faster responses to sensory stimuli when attentive and slower responses when distracted. Previous work suggested that contextual modulations may be implemented via top-down inputs to sensory cortex coming from higher brain areas or neuromodulatory pathways. Here, we introduce a theory explaining how the speed at which sensory cortex processes incoming information is adjusted by changes in these top-down projections, which control the timescale of neural activity. We tested our model predictions in freely running mice, revealing that locomotion accelerates visual processing. Our theory is applicable to internal modulation as well as optogenetic and pharmacological manipulations and links circuit connectivity, dynamics, and information processing.

Brain activation patterns in medicated versus medication-naïve adults with attention-deficit hyperactivity disorder during fMRI tasks of motor inhibition and cognitive switching.

BACKGROUND: Adult-attention-deficit-hyperactive-disorder (ADHD) is often unrecognized condition. FMRI examination along with neuropsychological testing might strengthen the diagnosis. We hypothesized that ADHD-adults with and without medication would show different fMRI pattern compared to healthy controls while testing tasks of motor inhibition and cognitive switching. METHODS: 45 subjects in three age-matched groups: (1) controls, (2) ADHD-adults under medication (ADHD+) and (3) medication-naïve adults with ADHD (ADHD-) underwent fMRI and neuropsychological testing. Group analysis and population-based statistics were performed. RESULTS: DTVP-A, intellectual ability as well as attention capability, visual-perceptual and visual-motor abilities showed no significant differences between the groups. However, fMRI revealed statistically significant differences between the ADHD+, ADHD- and control groups on tasks of motor inhibition and cognitive switching on adults in bilateral fronto-striatal brain regions, inferior fronto-frontal, fronto-cingulate and fronto-parietal networks as well as in the parietal lobe (p < 0.05). CONCLUSIONS: fMRI offers the potential to differentiate between the ADHD+, ADHD- and control groups. FMRI possibly opens a new window for monitoring the therapeutic effect of ADHD medication. TRIAL REGISTRATION: NCT02578342, registered at August 2015 to clinical trial registry ( https://ichgcp.net/clinical-trials-registry/NCT02578342 ).

Cholinergic manipulations affect sensory responses but not attentional enhancement in macaque MT.

BACKGROUND: Attentional modulation in the visual cortex of primates is characterized by multiplicative changes of sensory responses with changes in the attentional state of the animal. The cholinergic system has been linked to such gain changes in V1. Here, we aim to determine if a similar link exists in macaque area MT. While rhesus monkeys performed a top-down spatial attention task, we locally injected a cholinergic agonist or antagonist and recorded single-cell activity. RESULTS: Although we confirmed cholinergic influences on sensory responses, there was no additional cholinergic effect on the attentional gain changes. Neither a muscarinic blockage nor a local increase in acetylcholine led to a significant change in the magnitude of spatial attention effects on firing rates. CONCLUSIONS: This suggests that the cellular mechanisms of attentional modulation in the extrastriate cortex cannot be directly inferred from those in the primary visual cortex.

Perception-Action Integration Is Modulated by the Catecholaminergic System Depending on Learning Experience.

BACKGROUND: The process underlying the integration of perception and action is a focal topic in neuroscientific research and cognitive frameworks such as the theory of event coding have been developed to explain the mechanisms of perception-action integration. The neurobiological underpinnings are poorly understood. While it has been suggested that the catecholaminergic system may play a role, there are opposing predictions regarding the effects of catecholamines on perception-action integration. METHODS: Methylphenidate (MPH) is a compound commonly used to modulate the catecholaminergic system. In a double-blind, randomized crossover study design, we examined the effect of MPH (0.25 mg/kg) on perception-action integration using an established "event file coding" paradigm in a group of n = 45 healthy young adults. RESULTS: The data reveal that, compared with the placebo, MPH attenuates binding effects based on the established associations between stimuli and responses, provided participants are already familiar with the task. However, without prior task experience, MPH did not modulate performance compared with the placebo. CONCLUSIONS: Catecholamines and learning experience interactively modulate perception-action integration, especially when perception-action associations have to be reconfigured. The data suggest there is a gain control-based mechanism underlying the interactive effects of learning/task experience and catecholaminergic activity during perception-action integration.

Endogenous Opioid Signaling in the Mouse Retina Modulates Pupillary Light Reflex.

Opioid peptides and their receptors are expressed in the mammalian retina; however, little is known about how they might affect visual processing. The melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs), which mediate important non-image-forming visual processes such as the pupillary light reflex (PLR), express ß-endorphin-preferring, µ-opioid receptors (MORs). The objective of the present study was to elucidate if opioids, endogenous or exogenous, modulate pupillary light reflex (PLR) via MORs expressed by ipRGCs. MOR-selective agonist [D-Ala2, MePhe4, Gly-ol5]-enkephalin (DAMGO) or antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) was administered via intravitreal injection. PLR was recorded in response to light stimuli of various intensities. DAMGO eliminated PLR evoked by light with intensities below melanopsin activation threshold but not that evoked by bright blue irradiance that activated melanopsin signaling, although in the latter case, DAMGO markedly slowed pupil constriction. CTAP or genetic ablation of MORs in ipRGCs slightly enhanced dim-light-evoked PLR but not that evoked by a bright blue stimulus. Our results suggest that endogenous opioid signaling in the retina contributes to the regulation of PLR. The slowing of bright light-evoked PLR by DAMGO is consistent with the observation that systemically applied opioids accumulate in the vitreous and that patients receiving chronic opioid treatment have slow PLR.

Serotonergic Innervations of the Orbitofrontal and Medial-prefrontal Cortices are Differentially Involved in Visual Discrimination and Reversal Learning in Rats.

Cross-species studies have identified an evolutionarily conserved role for serotonin in flexible behavior including reversal learning. The aim of the current study was to investigate the contribution of serotonin within the orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC) to visual discrimination and reversal learning. Male Lister Hooded rats were trained to discriminate between a rewarded (A+) and a nonrewarded (B-) visual stimulus to receive sucrose rewards in touchscreen operant chambers. Serotonin was depleted using surgical infusions of 5,7-dihydroxytryptamine (5,7-DHT), either globally by intracebroventricular (i.c.v.) infusions or locally by microinfusions into the OFC or mPFC. Rats that received i.c.v. infusions of 5,7-DHT before initial training were significantly impaired during both visual discrimination and subsequent reversal learning during which the stimulus-reward contingencies were changed (A- vs. B+). Local serotonin depletion from the OFC impaired reversal learning without affecting initial discrimination. After mPFC depletion, rats were unimpaired during reversal learning but slower to respond at the stimuli during all the stages; the mPFC group was also slower to learn during discrimination than the OFC group. These findings extend our understanding of serotonin in cognitive flexibility by revealing differential effects within two subregions of the prefrontal cortex in visual discrimination and reversal learning.

Effects of the cannabinoid receptor 1 positive allosteric modulator GAT211 and acute MK-801 on visual attention and impulsivity in rats assessed using the five-choice serial reaction time task.

Altered interactions between endocannabinoid and glutamate signaling may be involved in the pathophysiology of schizophrenia and acute psychosis. As cognitive disturbances are involved in schizophrenia, increased understanding of the roles of these neurotransmitter systems in cognition may lead to the development of novel therapeutics for disorder. In the present study, we examined the effects of a recently synthesized cannabinoid receptor 1 (CB1R) positive allosteric modulator GAT211 in a rodent model of acute psychosis induced by systemic treatment with MK-801. To assess cognitive function, we used the Five-Choice Serial Reaction Time (5CSRT) task, conducted in touchscreen-equipped operant conditioning chambers. Our measures of primary interest were accuracy - indicative of visual attentional capacity - and the number of premature responses - indicative of impulsivity. We also measured latencies, omissions, and perseverative responding during all test sessions. Thirteen adult male Long Evans rats were trained on the 5CSRT and were then tested using a repeated measures design with acute MK-801 (0 or 0.15 mg/kg, i.p.) and GAT211 (0, 3, or 10 mg/kg, i.p.) administration. Acute MK-801 severely impaired accuracy, increased omissions, and increased the number of premature responses. MK-801 also significantly increased correct response latencies, without significant effects on incorrect or reward correction latencies. GAT211 had no significant effects when administered alone, or in combination with acute MK-801. These data confirm the dramatic effects of acute MK-801 treatment on behavioral measures of attention and impulsivity. Continued investigation of CB1R positive allosteric modulators as potential treatments for the cognitive symptoms of schizophrenia and related disorders should be pursued in other rodent models.

Dissociable contributions of mediodorsal and anterior thalamic nuclei in visual attentional performance: A comparison using nicotinic and muscarinic cholinergic receptor antagonists.

BACKGROUND: Thalamic subregions mediate various cognitive functions, including attention, inhibitory response control and decision making. Such neuronal activity is modulated by cholinergic thalamic afferents and deterioration of such modulatory signaling has been theorised to contribute to cognitive decline in neurodegenerative disorders. However, the thalamic subnuclei and cholinergic receptors involved in cognitive functioning remain largely unknown. AIMS: We investigated whether muscarinic or nicotinic receptors in the mediodorsal thalamus and anterior thalamus contribute to rats' performance in the five-choice serial reaction time task, which measures sustained visual attention and impulsive action. METHODS: Male Long-Evans rats were trained in the five-choice serial reaction time task then surgically implanted with guide cannulae targeting either the mediodorsal thalamus or anterior thalamus. Reversible inactivation of either the mediodorsal thalamus or anterior thalamus were achieved with infusions of the γ-aminobutyric acid-ergic agonists muscimol and baclofen prior to behavioural assessment. To investigate cholinergic mechanisms, we also assessed the behavioural effects of locally administered nicotinic (mecamylamine) and muscarinic (scopolamine) receptor antagonists. RESULTS: Reversible inactivation of the mediodorsal thalamus severely impaired discriminative accuracy and response speed and increased omissions. Inactivation of the anterior thalamus produced less profound effects, with impaired accuracy at the highest dose. In contrast, blocking cholinergic transmission in these regions did not significantly affect five-choice serial reaction time task performance. CONCLUSIONS/INTERPRETATIONS: These findings show the mediodorsal thalamus plays a key role in visuospatial attentional performance that is independent of local cholinergic neurotransmission.

Intravitreous delivery of melatonin affects the retinal neuron survival and visual signal transmission: in vivo and ex vivo study.

Intravitreal delivery can maximize the intensity of therapeutic agents and extend their residence time within ocular tissue. Melatonin is a lipophilic molecule that crosses freely biological barriers and cell membranes. This study intends to investigate the effects of intravitreally delivered melatonin on mouse retina. The visual function of administered mice is assessed by electrophysiological and behavior examinations three weeks after intravitreal delivery. Moreover, multi-electrode array (MEA) was used to assess the electrical activities of retinal ganglion cells (RGCs). We found that intravitreal delivery of high dosage melatonin (400-500 µg/kg) destroyed the retinal architecture and impaired the visual function of mice. Conversely, the melatonin administration at low dose (100-300 µg/kg) did not have any significant effects on the photoreceptor survival or visual function. As shown in the MEA recording, the photoreceptors activity of the central region was more severely disturbed by the high dose melatonin. A pronounced augment of the spontaneous firing frequency was recorded in these mice received high dosage melatonin, indicating that intravitreal delivery of high dosage melatonin would affect the electrical activity of RGCs. Immunostaining assay showed that the vitality of cone photoreceptor was impaired by high dose melatonin. These findings suggest that intravitreal melatonin is not always beneficial for ocular tissues, especially when it is administered at high dosage. These data add new perspectives to current knowledge about melatonin delivery at the ocular level. Further therapeutic strategies should take into consideration of these risks that caused by delivery approach.

Moderate Prenatal Alcohol Exposure Impairs Visual-Spatial Discrimination in a Sex-Specific Manner: Effects of Testing Order and Difficulty on Learning Performance.

BACKGROUND: Exposure to high levels of alcohol during development leads to alterations in neurogenesis and deficits in hippocampal-dependent learning. Evidence suggests that even more moderate alcohol consumption during pregnancy can have negative impacts on the cognitive function of offspring. Methods for assessing impairments differ greatly across species, complicating translation of preclinical findings into potential therapeutics. We have demonstrated the utility of a touchscreen operant measure for assessing hippocampal function in mice. METHODS: Here, we integrated a well-established "drinking-in-the-dark" exposure model that produces reliable, but more moderate, levels of maternal intoxication with a trial-unique, delayed nonmatching-to-location (TUNL) task to examine the effects of prenatal alcohol exposure (PAE) on hippocampal-sensitive behavior directly analogous to those used in clinical assessment. PAE and SAC offspring mice were trained to touch a single visual stimulus ("sample phase") in one of 10 possible spatial locations (2 × 5 grid) in a touchscreen operant system. After a delay, animals were simultaneously presented with the original stimulus and a rewarded stimulus in a novel location ("choice phase"). PAE and saccharin (SAC) control mice were trained on a series of problems that systematically increased the difficulty by decreasing the separation between the sample and choice stimuli. Next, a separate cohort of PAE and SAC animals were given a brief training and then tested on a challenging variant where both the separation and delay varied with each trial. RESULTS: We found that PAE mice were generally able to perform at levels similar to SAC control mice at progressively more difficult separations. When tested on the most difficult unpredictable variant immediately, PAE showed a sex-specific deficit with PAE females performing worse during long delays. CONCLUSIONS: Taken together, these data demonstrate the utility of the TUNL task for examining PAE related alterations in hippocampal function and underline the need to examine sex-by-treatment interactions in these models.