Biology subjects

Loayza, J.

Publications and source records attributed to Loayza, J..

4 recordsLinked to original sources

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↗

bioRxiv2025

Too little and too much: medial prefrontal functional inhibition impairs early acquisition of operant reversal learning, whereas medial prefrontal disinhibition impairs established serial-reversal performance in rats

Schizophrenia is associated with reduced activation ( hypofrontality) and neural disinhibition (reduced GABAergic inhibition) in the dorsolateral prefrontal cortex (dlPFC), as well as reversal learning deficits. Whilst reversal learning has been strongly linked to the orbitofrontal cortex, its dependence on the primate dlPFC - and its rodent analogue, the medial PFC (mPFC) - is less clear. Nevertheless, we hypothesized that the mPFC may be required for reversal learning if the reversal is demanding. Furthermore, even if the mPFC is not required, mPFC disinhibition may impair reversals, because it may disrupt processing in mPFC projection sites. To test these hypotheses, we combined bi-directional manipulations of mPFC GABAergic inhibition, using intracerebral drug microinfusion and chemogenetic/DREADD methods, with reversal testing on a food-reinforced two-lever discrimination task in rats. First, we induced mPFC functional inhibition and disinhibition, by microinfusion of the GABA-A receptor agonist muscimol or antagonist picrotoxin, respectively, and examined the impact on early reversals (reversals 1-3) and well-established serial reversals (reversal 5 onwards). Using classical performance measures and Bayesian trial-by-trial strategy analysis, we found that mPFC muscimol impaired early, but not serial, reversals, increasing perseveration and impairing exploratory (lose-shift) behavior at reversal 2. In contrast, mPFC picrotoxin impaired serial reversals, reducing exploratory (lose-shift) and exploitative (win-stay) behavior. Second, to inhibit mPFC GABAergic neurons, we expressed the inhibitory DREADD hM4Di in these neurons; chemogenetic mPFC disinhibition by activation of hM4Di also impaired serial reversal learning, primarily disrupting exploitation. Our findings suggest that mPFC hypoactivation and disinhibition disrupt distinct aspects of reversal learning by different mechanisms. Significance statementSchizophrenia is associated with reduced activation ("hypofrontality") and neural disinhibition (reduced GABAergic inhibition) within the prefrontal cortex (PFC). Yet, it is not clear if and how these distinct aspects of prefrontal dysfunction contribute to impaired reversal learning, a key feature of the cognitive inflexibility characterizing schizophrenia. Here, we combined bi-directional manipulations of prefrontal GABAergic inhibition with testing of reversal learning in rats. Increasing prefrontal functional inhibition (i.e., reducing prefrontal activation) selectively impaired early reversals, enhancing perseveration and reducing exploratory (lose-shift) behavior, whereas prefrontal disinhibition disrupted serial reversals, impairing both exploration and exploitation. Our findings suggest that reduced activation and disinhibition of PFC disrupt distinct aspects of reversal learning, by distinct mechanisms.

neuroscience↗

bioRxiv2025

Neuro-behavioral impact of Tourette-related striatal disinhibition in rats

Tourette syndrome has been linked to reduced GABAergic inhibition, so called neural disinhibition, in the dorsal striatum. Dorsal-striatal neural disinhibition in animal models, caused by local microinfusion of GABA-A-receptor antagonists, produces striatal local field potential (LFP) spike-wave discharges and tic-like movements resembling motor tics. Here, we characterized further the neuro-behavioral impact of striatal disinhibition, by unilateral picrotoxin infusion into the anterior dorsal striatum, in adult male Lister hooded rats. In vivo electrophysiology under anesthesia revealed enhanced neuronal burst firing in the striatum, alongside spike-wave LFP discharges. In freely moving rats, striatal picrotoxin reliably induced tic-like movements, which mainly involved lifting of the contralateral forelimb and concomitant rotational movements of head and torso, as well as occasional rotations of the whole body around its long axis. Prepulse inhibition (PPI) of the acoustic startle response was not affected, but startle reactivity tended to be reduced. Both locomotor and non-ambulatory movements, measured in photo-beam cages, were increased. Our findings suggest that, apart from generating tic-like movements, dorsal striatal disinhibition may contribute to hyperactivity, which is often comorbid with Tourette syndrome. Enhanced striatal burst firing may be important for these behavioral effects. Our findings do not support that striatal disinhibition contributes to PPI disruption, which has been associated with Tourette syndrome and suggested to contribute to tic generation. Significance StatementStriatal disinhibition has been implicated in tic generation. Using a rat model, we show that a key neural effect of striatal disinhibition is enhanced firing of striatal neurons in bursts. We also characterized further the tic-like movements caused by unilateral disinhibition of the anterior dorsal striatum. These mainly involved lifting of the contralateral forelimb and concomitant rotational movements of head and torso, as well as occasional rotations of the whole body around its long axis. Striatal disinhibition did not affect prepulse inhibition (PPI) but caused locomotor hyperactivity. This suggests that striatal disinhibition may contribute to the general hyperactivity often comorbid with Tourette syndrome, but that other brain mechanisms underlie the PPI deficits that have been reported in the condition.

neuroscience↗

bioRxiv2021

Hippocampal disinhibition reduces contextual and elemental fear conditioning while sparing the acquisition of latent inhibition

Hippocampal neural disinhibition, i.e. reduced GABAergic inhibition, is a key feature of schizophrenia pathophysiology. The hippocampus is an important part of the neural circuitry that controls fear conditioning and can also modulate prefrontal and striatal mechanisms, including dopamine signalling, which play a role in salience modulation. Therefore, hippocampal neural disinhibition may contribute to impairments in fear conditioning and salience modulation reported in schizophrenia. To test this hypothesis, we examined the effect of ventral hippocampus (VH) disinhibition in male rats on fear conditioning and salience modulation, as reflected by latent inhibition (LI), in a conditioned emotional response procedure (CER). A flashing light was used as the conditioned stimulus (CS) and conditioned suppression was used to index conditioned fear. In Experiment 1, VH disinhibition via infusion of the GABA-A receptor antagonist picrotoxin prior to CS pre-exposure and conditioning markedly reduced fear conditioning to both the CS and context; LI was evident in saline-infused controls, but could not be detected in picrotoxin-infused rats due to the low level of fear conditioning to the CS. In Experiment 2, VH picrotoxin infusions prior to CS pre-exposure only did not affect the acquisition of fear conditioning or LI. Together, these findings indicate that VH neural disinhibition disrupts contextual and elemental fear conditioning, without affecting the acquisition of LI. The disruption of fear conditioning resembles aversive conditioning deficits reported in schizophrenia and may reflect disruption of neural processing within the hippocampus and its projection sites. Significance StatementHippocampal disinhibition, reduced GABAergic inhibition, is a feature of schizophrenia, but how this contributes to psychological deficits remains to be clarified. Here, we focused on impairments patients show on classical-conditioning assays: aberrant salience allocation to stimuli that healthy participants have learnt to ignore and reduced fear conditioning, which have been linked to psychosis and negative symptoms, respectively. These impairments may be related to hippocampal disinhibition because the hippocampus modulates neural substrates of salience allocation and is part of the fear-conditioning neural circuit. Combining selective pharmacological manipulation of the hippocampus with a conditioning assay in rats, we found hippocampal disinhibition disrupted fear conditioning, without evidence for aberrant salience allocation. This suggests hippocampal disinhibition contributes to fear conditioning deficits in schizophrenia.

neuroscience↗