Biology subjects

Gigg, J.

Publications and source records attributed to Gigg, J..

10 recordsLinked to original sources

bioRxiv2026

Rate dependent Effects of AMPH on attentional processes as measured by 5C-CPT task

Background: ADHD is characterized by inattention and impulsivity. Stimulants such as amphetamine are the first line treatments for ADHD. Amphetamine (AMPH) works by increasing extracellular levels of dopamine and noradrenaline. Such stimulants are used to test predictive validity of animal tasks, where it has been reported that amphetamine improves rat 5-CSRTT accuracy when the session length is increased to 250 trials. This improvement in accuracy was observed later in the session as control performance declined. Proving that amphetamine can improve 5C-CPT task performance adds to the predictive validity of the task. No previous works has demonstrated the pro-attentional effects of amphetamine on sustained attention in rat 5C-CPT. We have previously shown that pharmacological manipulations of dopaminergic system improve waiting impulsivity in a rate dependent manner and the importance of analysing the data using Oldham method. The present study extends this work to investigate the effect of amphetamine on attentional processes. Objective: to investigate effects of amphetamine on attentional processes as measured by 5C-CPT task using correlational analysis and group performance. Methods: Trained female Lister hooded rats were tested with AMPH (0.1, 0.2 and 0.4 mg/kg) under reduced stimulus duration schedule (0.25,0.5,1,1.5 and 2s SD) over normal length session (120 trials). Correlational analysis (Oldham method) was used to understand the relationship between baseline performance measures and the change following administration of AMPH. Results: The highest dose of AMPH impaired attentional performance in the 5C-CPT under reduced SD challenge (0.5s,1s,1.5s and 2s). This impairment was due to increase in FAR. Previous studies in 5-CSRTT suggest that reducing the SD increases attentional demand in the form of reducing accuracy without affecting waiting impulsivity. However, the 5-CSRTT does not include non-target trials, therefore, it cannot be used to measure sustained attention (SI) and responsivity index. The 5C-CPT requires greater attentional resources than the 5-CSRTT.This study is the first to report that reducing the SD changes responsivity index (bias) rather than measures of sustained attention (sensitivity index) in the 5C-CPT. Control sensitivity index did not change until the SD was reduced to less than 0.5s and this change was due to a change in baseline responsivity index (bias). Performance under each reduced SD revealed that the highest dose of AMPH (0.4 mg/kg) showed a tendency toward reducing sensitivity index at 0.5, 1.0 and 1.5s SDs. Under 1.0s SD, the highest dose of AMPH changed sustained attention (SI, HR and FAR) and omission in a rate-dependent manner without changing responsivity index. Performance across the session revealed that the impairment in sustained attention was observed at the beginning of the session. In the third trial block, Oldham method revealed an inverse relationship between baseline accuracy and the change following administration of 0.2 mg/kg AMPH, indicative of a rate-dependent effect. Conclusions: This study successfully demonstrates rate-dependent effects of AMPH on measures of attentional performance in the 5C-CPT. This experiment also demonstrates that responsivity index is sensitive to reduced SD challenge. To our knowledge this is the first study to report the presence of a direct relationship between baseline sustained attention and magnitude of improvement following administration of 0.4 mg/kg AMPH and an inverse relationship between baseline accuracy and the change following administration of 0.2 mg/kg AMPH in 5C-CPT task. Future studies should test lower doses of amphetamine (0.05 and 0.1 mg/kg) over extended session length (250 trials) to reveal the pro-attentional effects of this drug on 5C-CPT performance measures.

animal behavior and cognition↗

bioRxiv2025

Too little and too much: balanced hippocampal, but not medial prefrontal, neural activity is required for intact novel object recognition in rats

Impaired GABAergic inhibition, so-called neural disinhibition, in the prefrontal cortex and hippocampus has been linked to cognitive deficits. The novel object recognition (NOR) task has been used widely to study cognitive deficits in rodents. However, the contribution of prefrontal cortex and hippocampal GABAergic inhibition to NOR task performance has not been established. Here, we investigated NOR task performance in male Lister Hooded rats following regional neural disinhibition or functional inhibition, using intra-cerebral microinfusion of the GABA-A receptor antagonist picrotoxin or agonist muscimol, respectively. Our infusion targets were the medial prefrontal cortex (mPFC), dorsal hippocampus and ventral hippocampus. Using a within-subjects design, we compared NOR task performance (1-min retention delay) following bilateral regional saline, picrotoxin or muscimol infusions made before the acquisition phase. In mPFC, neither functional inhibition nor neural disinhibition affected object recognition memory. However, in both dorsal and ventral hippocampus, neural disinhibition impaired NOR relative to saline control, mainly by reducing novel object exploration time. In addition, functional inhibition of dorsal hippocampus impaired NOR, whereas ventral hippocampal functional inhibition tended to reduce novel object exploration at the highest dose used (alongside substantial non-specific behavioural effects). Overall, our data suggest that hippocampal, but not prefrontal, GABAergic inhibition contributes to NOR at a 1-min retention delay. Moreover, such NOR performance likely requires balanced neural activity in the dorsal hippocampus, with both too little and too much dorsal hippocampal activity impairing NOR memory. Our findings support that the NOR task can be used to investigate hippocampal GABAergic dysfunction in rodent models. Significance statementImpaired GABAergic neural inhibition in the prefrontal cortex and hippocampus has emerged as a key neuropathological feature of cognitive disorders. The novel object recognition (NOR) task is used widely in rodent models to investigate cognitive impairments relevant to cognitive disorders. However, the role of hippocampal and prefrontal GABAergic inhibition in NOR is unclear, limiting interpretations as to how NOR deficits in rodent models may relate to this key pathological feature of many cognitive disorders. Here, we show that impaired hippocampal GABAergic inhibition impairs NOR in rats, whereas prefrontal GABAergic inhibition is not required. Thus, the NOR task may be used to investigate hippocampal GABAergic dysfunction in rodent models.

neuroscience↗

bioRxiv2024

Executive dysfunction is associated with altered hippocampal-prefrontal functional connectivity in male 3xTg Alzheimer's model mice

Executive function depends on connectivity between the ventral hippocampus and medial prefrontal cortex (mPFC). How abnormalities in this pathway lead to cognitive dysfunction in Alzheimers disease (AD) have yet to be elucidated. Here, male 3xTg AD mice at 6-months displayed maladaptive decision-making in the rodent 4-Choice Gambling Task measure of executive function. Extracellular field recordings in the infralimbic cortex at this age showed layer-specific reductions in response amplitude and paired-pulse ratio following activation of hippocampal input fibres, indicating changes to short-term hippocampal-prefrontal synaptic plasticity. Bulk RNA sequencing of the mPFC in 6-month-old mice identified differential gene expression changes associated with calcium ion transport, glutamatergic, GABAergic, and dopaminergic neurotransmission. Seven of these genes (Gpm6b, Slc38a5, Ccr5, Kcnj10, Ddah1, Gad1, Slc17a8) were also differentially expressed in 3-month mice. These results reveal a pre-clinical deficit in executive function correlating with synaptic plasticity and gene expression changes in the mPFC of male 3xTg mice.

neuroscience↗

bioRxiv2024

Effects of D3-preferring agonist PD 128907 on compulsive behaviour and decision making as assessed by the 5C-CPT

BackgroundRepetitive rituals in OCD patients result from pathological doubt, which has been linked to dysfunction in decision-making. First-line drug treatments for OCD are selective serotonin reuptake inhibitors; however, 40% of OCD patients do not respond to these. As brain activity patterns in OCD resemble those in schizophrenic patients, this suggests a dopaminergic component, supported by data showing that the D2/D3 receptor agonist Quinpirole induces compulsive checking in male rats. OCD has proved difficult to model in rodents and the contribution of decision making to compulsive behaviour in such models has not been studied. The five-choice continuous performance task (5C-CPT) measures both decision making and compulsive behaviour, making it possible to evaluate whether OCD models show correlated changes in these two behaviours. Establishing this would provide a new model approach to help develop therapeutic agents for OCD. AimsThe role of dopaminergic D3 receptors in decision making and compulsive behaviour was determined by testing the effect of the preferential D3 agonist PD 128907 on 5C-CPT performance measures. Oldhams method was used to determine the presence of any rate-dependent effect. MethodsFemale Lister hooded rats were trained to criterion in the 5C-CPT (>70% accuracy, < 30% omission and < 40% false alarms). The effects of PD128907 (0.25-1 mg/kg) were then investigated under challenging task conditions. ResultsOldham method revealed: a moderate positive association between baseline perseverative correct responses and the change at 0.05 mg/kg PD 128907; a strong positive association between baseline perseverative false alarm and the change at 0.2 mg/kg; a positive association between baseline total number of perseverative responses and the change at 0.05 mg/kg or 0.2 mg/kg PD 128907; a positive relationship between baseline accuracy and the change at 0.05 mg/kg PD 128907; and a moderate positive association between baseline correct response latency and the change at 0.05 mg/kg or 0.2 mg/kg PD 128907. The angle measurements and the direction of movement (clockwise or counterclockwise) showed how effective is one dose at increasing compulsive behaviour compared with other doses. ConclusionsPD 128907 effects on compulsive like behaviour and decision making in poor performing female lister hooded rats with long correct response latency and high perseveration at baseline (vulnerable population) in the 5C-CPT task matches two key features of OCD compulsions in humans (perseveration and indecision), this suggests that PD 128907 is more effective than Quinpirole in simulating the brain network conditions that underpin OCD. This model could help to develop more successful pharmacological interventions and to generate data translatable to clinical studies.

animal behavior and cognition↗

bioRxiv2023

Rate dependent effects of SKF 38393 and amphetamine on waiting impulsivity in the 5C-CPT

RationaleStimulants are the first-line treatment for attention-deficit/hyperactivity disorder (ADHD). However, the ensuing risk of abuse with stimulants means there is an urgent need for new, low-risk therapeutic agents. D1 receptors play an important role in the cognitive enhancing effects of stimulants and thus may provide a therapeutic target. Previous pre-clinical studies have shown that selective activation of D1 receptors improves sustained attention in the 5C-CPT without improving waiting impulsivity (premature response). ObjectiveThe aim of the present experiment was to compare the effects of the selective D1 receptor agonist SKF 38393 to a standard ADHD treatment (amphetamine) on waiting impulsivity in the 5C-CPT under extended inter-trial intervals. Oldhams method was used to determine the presence of a rate-dependent effect. MethodsAdult female Lister hooded rats were trained to criterion in the 5C-CPT (>70% accuracy, < 30% omission and < 40% false alarms). Effects of the selective D1 receptor agonist SKF 38393 (2-6 mg/kg) or amphetamine (0.1-0.4 mg/kg) were investigated under behavioural manipulations to challenge inhibitory response control. ResultsThe highest dose of SKF 38393 and the two highest doses of amphetamine improved waiting impulsivity in a baseline dependent manner. The clockwise movement of the regression line indicates that, as the dose increases, the magnitude of improvement increases in a manner consistent with baseline performance. ConclusionsThese findings support further clinical investigation of D1 receptor modulators to facilitate the discovery of improved medications for impulsive behaviour related disorders such as ADHD. The concept of rate dependency applies to effects of SKF 38393 or amphetamine on waiting impulsivity. Oldhams correlation method may present an opportunity to enhance the translational value of research in the preclinical laboratory to the clinic.

animal behavior and cognition↗

bioRxiv2023

The dopamine inhibitor GBR12909 improves attention and compulsive behaviour in female rats

BackgroundStimulants such as methylphenidate are the first-line treatment for attention deficit hyperactivity disorder (ADHD). A principal mechanism of action for these drugs is to reduce dopamine reuptake in the striatum. However, the ensuing risk of abuse with such stimulants means there is an urgent need for new, low-risk therapeutic agents. GBR12909 is a highly selective dopamine reuptake inhibitor, making it an important experimental tool. Indeed, this drug completed Phase II clinical trials for treatment of cocaine abuse. Understanding such drugs has the potential to expand our understanding of the striatal dopamine contribution to impulsivity, attention and compulsive behaviour and will help the development of novel targeted treatments for ADHD without an abuse risk. AimsThe aim of this work was to examine the role of low doses of GBR12909 on attention, impulsivity and compulsive behaviour as measured by 5C-CPT. Oldhams methods was used to determine the presence of a rate-dependent effect. MethodsFemale Lister hooded rats were trained to criterion in the 5C-CPT (>70% accuracy, < 30% omission and < 40% false alarms). Effects of GBR12909 (0.25-1 mg/kg) were investigated on attention, impulsivity and compulsive behaviour under challenging task conditions. ResultsThe two lowest doses of GBR12909 improved selective attention in a rate-dependent manner while the highest dose of GBR 12909 showed a tendency toward improving compulsive behaviour in a baseline-dependent manner. However, GBR 12909 impaired waiting impulsivity in a baseline-dependent manner. ConclusionsGBR12909 has a clearly beneficial effect on attention and compulsive behaviour in the female rat. These findings support further clinical investigation of GBR-type dopamine uptake blockers or GBR analogues to facilitate the discovery of medications for inattentive ADHD, stimulant abuse, compulsive drug seeking behaviour and obsessive-compulsive disorder.

animal behavior and cognition↗

bioRxiv2021

Functional ultrasound imaging of recent and remote memory recall in the associative fear neural network in mice

Scientific AbstractEmotional learning and memory are affected in numerous psychiatric disorders. At a systems level, however, the underlying neural circuitry is not well defined. Rodent fear conditioning (FC) provides a translational model to study the networks underlying associative memory retrieval. In the current study, functional connectivity among regions related to the cue associative fear network were investigated using functional ultrasound (fUS), a novel imaging technique with great potential for detecting regional neural activity through cerebral blood flow. Behavioral fear expression and fUS imaging were performed one and thirty-one days after FC to assess recent and remote memory recall. Cue-evoked increases in functional connectivity were detected throughout the amygdala, with the lateral (LA) and central (CeA) amygdalar nuclei emerging as major hubs of connectivity, though CeA connectivity was reduced during remote recall. The hippocampus and sensory cortical regions displayed heightened connectivity with the LA during remote recall, whereas interconnectivity between the primary auditory cortex and temporal association areas was reduced. Subregions of the prefrontal cortex exhibited variable connectivity changes, where prelimbic connectivity with the amygdala was refined while specific connections between the infralimbic cortex and amygdalar subregions emerged during remote memory retrieval. Moreover, freezing behavior positively correlated with functional connectivity between hubs of the associative fear network, suggesting that emotional response intensity reflected the strength of the cue-evoked functional network. Overall, our data provide evidence of the functionality of fUS imaging to investigate the neural dynamics of memory encoding and retrieval, applicable in the development of innovative treatments for affective disorders. HighlightsFunctional ultrasound imaging can elucidate fear associated neural networks Freezing behavior correlates with cue-evoked functional connectivity changes The lateral and central amygdalar nuclei are major hubs in the fear network The hippocampus is active during recent and remote cued fear memory retrieval Connectivity profiles of the prelimbic and infralimbic areas vary in remote recall

neuroscience↗

bioRxiv2020

Dissociating the effects of distraction and proactive interference on object memory through tests of novelty preference

Encoding information into memory is sensitive to distraction whilst retrieving that memory may be compromised by proactive interference from pre-existing memories. These two debilitating effects are common in neuropsychiatric conditions but modelling them preclinically to date is slow as it requires prolonged operant training. A step change would be the validation of functionally equivalent but fast, simple, high-throughput tasks based on spontaneous behaviour. Here, we show that spontaneous object preference testing meets these requirements in the subchronic phencyclidine (scPCP) rat model for cognitive impairments associated with schizophrenia. scPCP rats show clear memory sensitivity to distraction in the standard novel object recognition task (stNOR). However, due to this, stNOR cannot assess proactive interference. Therefore, we compared scPCP performance in stNOR to that using the continuous NOR task (conNOR), which offers minimal distraction, allowing disease-relevant memory deficits to be assessed directly. We first determined that scPCP treatment did not affect whisker movements during object exploration. scPCP rats exhibited the expected distraction stNOR effect but had intact performance on the first conNOR trial, effectively dissociating distraction by using two NOR task variants. In remaining conNOR trials, scPCP rats performed above chance throughout but, importantly, their detection of object novelty was increasingly impaired relative to controls. We attribute this effect to the accumulation of proactive interference. This is the first demonstration that increased sensitivity to distraction and proactive interference, both key cognitive impairments in schizophrenia, can be dissociated in the scPCP rat using two variants of the same fast, simple, spontaneous object memory paradigm.

animal behavior and cognition↗

bioRxiv2020

Local and global dichotomic dysfunction in resting and evoked functional connectivity precedes tauopathy

Functional network activity alterations are one of the earliest hallmarks of Alzheimers disease (AD), detected prior to amyloidosis and tauopathy. Better understanding the neuronal underpinnings of such network alterations could offer mechanistic insight into AD progression. Here, we examined a mouse model (early-tauopathy 3xTgAD mice) recapitulating this early AD stage. We found resting functional connectivity loss within ventral networks, including the entorhinal cortex, aligning with the spatial distribution of tauopathy reported in humans. Unexpectedly, in contrast to decreased connectivity at rest, 3xTgAD mice show enhanced fMRI signal within several projection areas following optogenetic activation of the entorhinal cortex. We corroborate this finding by demonstrating neuronal facilitation within ventral networks and synaptic hyperexcitability in projection targets. 3xTgAD mice thus reveal a dichotomic hypo-connected resting/hyper-responsive active phenotype. The strong homotopy between the areas affected supports the translatability of this pathophysiological model to tau-related deficits in humans.

neuroscience↗

bioRxiv2018

A new test of value-modulated attentional bias in mice

The allocation of attention can be modulated by the emotional value of a stimulus. In order to understand the biasing influence of emotion on attention allocation further, we require an animal test of how motivational salience modulates attention. In mice, female odour triggers arousal and elicits emotional responses in males. Here, we determined the extent to which objects labelled with female odour modulated the attention of C57BL/6J male mice. Seven experiments were conducted, using a modified version of the spontaneous Novel Object Recognition task. Attention was operationalised as differential exploration time of identical objects that were labelled with either female mouse odour (O+), a non-social odour, almond odour (Oa) or not labelled with any odour (O-). In some experiments we tested trial unique (novel) objects than never carried an odour (X-). We found that when single objects were presented, as well as when two objects were presented simultaneously (so competed with each other for attention), O+ received preferential attention compared to O-. This result was independent of whether O+ was at a novel or familiar location. When compared with Oa at a novel location, O+ at a familiar location attracted more attention. Compared to X-, O+ received more exploration only when placed at a novel location, but attention to O+ and X- was equivalent when they were placed in a familiar location. These results suggest that C57BL/6J male mice weigh up aspects of odour, object novelty and special novelty for motivational salience, and that, in some instances, female odour elicits more attention (object exploration) compared to other olfactory stimuli and visual object novelty. The findings of this study pave the way to using motivationally-significant odours to modulate the cognitive processes that give rise to novel object recognition.

neuroscience↗