Biology subjects

Mingote, S.

Publications and source records attributed to Mingote, S..

6 recordsLinked to original sources

bioRxiv2026

Dissecting the Role of the Lateral Entorhinal Cortex in Memory Interference

Memory interference occurs when an older memory competes with a newer memory that shares similar features 1. The hippocampal-entorhinal system is essential for memory 2,3, and the entorhinal cortex has been implicated in interference using the latent inhibition paradigm 4. In latent inhibition, prior non-reinforced exposure to a stimulus reduces the conditioned response later elicited when that same stimulus is paired with an aversive or appetitive outcome 5. Competition-based models propose that latent inhibition arises because the memory that the pre-exposed stimulus was inconsequential competes during retrieval with the memory that the same stimulus predicts an unconditioned stimulus 6. Although entorhinal cortex lesions or inactivation impair latent inhibition 7-10, the specific contribution of the lateral entorhinal cortex (LEC) remains unclear. The LEC provides non-spatial and cue-related input to the hippocampus 11 and has been implicated in associative memory 12,13. LEC function also declines with age 14,15, a period when memory interference increases 16. Here, we used chemogenetics to transiently inhibit excitatory neurons in the LEC during retrieval in a latent inhibition paradigm. LEC inhibition did not impair conditioned fear responses to a non-pre-exposed tone, indicating that retrieval of the tone-shock association remained intact. However, LEC inhibition attenuated latent inhibition by increasing conditioned fear responses to a pre-exposed tone. Together, these findings suggest that the LEC supports retrieval of prior inconsequential stimulus memories that compete with newer conditioned associations, providing a potential mechanism by which age-related LEC dysfunction may contribute to increased memory interference. HighlightsO_LIPre-exposure to a tone attenuates retrieval of a tone-evoked conditioned fear response, revealing latent inhibition C_LIO_LILateral entorhinal cortex inhibition does not impair fear-memory retrieval in non-pre-exposed animals C_LIO_LIThe lateral entorhinal cortex is required for the expression of latent inhibition during retrieval C_LIO_LIThe lateral entorhinal cortex contributes to memory interference during retrieval of stimuli with conflicting associations C_LI In BriefGhazy et al. show that the lateral entorhinal cortex (LEC) is required for latent inhibition during retrieval, in which prior tone exposure attenuates later fear responding to that same tone. Because LEC inhibition does not impair tone-evoked conditioned fear responding, these findings indicate that the LEC contributes to memory interference when the same stimulus has conflicting associations.

neuroscience↗

bioRxiv2025

Evidence for age-related vulnerability in dopamine-glutamate projections to the lateral entorhinal cortex

The lateral entorhinal cortex (LEC) supports novelty detection and episodic memory and is selectively vulnerable to aging. Dopamine signals novelty in LEC, but how aging alters this input is unclear. Using intersectional viral strategies to distinguish ventral tegmental area (VTA) dopamine neurons with or without glutamate co-release, we find that co-releasing neurons are a minority ([~]30%) in the VTA, yet provide [~]93% of the dopaminergic projections to LEC. In aged mice, dopamine-glutamate labeling in VTA and LEC decreases [~]80%, whereas pan-dopaminergic labeling of LEC axons remains, consistent with functional silencing rather than degeneration. In LEC dopaminergic axons, dopamine synthesis is reduced while glutamate vesicular packaging is relatively spared. Optogenetic stimulation combined with a dopamine sensor reveals diminished dopamine release at high frequencies, when synthesis demand is greatest. These findings identify selective vulnerability of dopamine-glutamate neurons as a cell- and circuit-specific mechanism that weakens dopamine signaling within memory circuits.

neuroscience↗

bioRxiv2023

Role of Dopamine Neurons in Familiarity

Dopamine neurons signal the salience of environmental stimuli, influencing learning and motivation. However, research has not yet identified whether dopamine neurons also modulate the salience of memory content. Dopamine neuron activity in the ventral tegmental area (VTA) increases in response to novel objects and diminishes as objects become familiar through repeated presentations. We proposed that the declined rate of dopamine neuron activity during familiarization affects the salience of a familiar objects memory. This, in turn, influences the degree to which an animal distinguishes between familiar and novel objects in a subsequent novel object recognition (NOR) test. As such, a single familiarization session may not sufficiently reduce dopamine activity, allowing the memory of a familiar object to maintain its salience and potentially attenuating NOR. In contrast, multiple familiarization sessions could lead to more pronounced dopamine activity suppression, strengthening NOR. Our data in mice reveals that, compared to a single session, multiple sessions result in decreased VTA dopamine neuron activation, as indicated by c-Fos measurements, and enhanced novelty discrimination. Critically, when VTA dopamine neurons are chemogenetically inhibited during a single familiarization session, NOR improves, mirroring the effects of multiple familiarization sessions. In summary, our findings highlight the pivotal function of dopamine neurons in familiarity and suggest a role in modulating the salience of memory content.

animal behavior and cognition↗

bioRxiv2023

Sexually dimorphic mechanisms of VGLUT-mediated protection from dopaminergic neurodegeneration

Parkinsons disease (PD) targets some dopamine (DA) neurons more than others. Sex differences offer insights, with females more protected from DA neurodegeneration. The mammalian vesicular glutamate transporter VGLUT2 and Drosophila ortholog dVGLUT have been implicated as modulators of DA neuron resilience. However, the mechanisms by which VGLUT2/dVGLUT protects DA neurons remain unknown. We discovered DA neuron dVGLUT knockdown increased mitochondrial reactive oxygen species in a sexually dimorphic manner in response to depolarization or paraquat-induced stress, males being especially affected. DA neuron dVGLUT also reduced ATP biosynthetic burden during depolarization. RNA sequencing of VGLUT+ DA neurons in mice and flies identified candidate genes that we functionally screened to further dissect VGLUT-mediated DA neuron resilience across PD models. We discovered transcription factors modulating dVGLUT-dependent DA neuroprotection and identified dj-1{beta} as a regulator of sex-specific DA neuron dVGLUT expression. Overall, VGLUT protects DA neurons from PD-associated degeneration by maintaining mitochondrial health.

neuroscience↗

bioRxiv2018

Substantia nigra dopamine neurons evoke a delayed excitation in lateral dorsal striatal cholinergic interneurons via glutamate cotransmission

Dopamine neurons have different synaptic actions in the ventral and dorsal striatum (dStr), but whether this heterogeneity extends to dStr subregions has not been addressed. We have found that optogenetic activation of dStr dopamine neuron terminals in mouse brain slices pauses the firing of cholinergic interneurons in both the medial and lateral subregions, while in the lateral subregion the pause is shorter due to a subsequent excitation. This excitation is mediated mainly by metabotropic glutamate receptor 1 (mGluR1) and partially by dopamine D1-like receptors coupled to transient receptor potential channel 3 and 7. DA neurons do not signal to spiny projection neurons in the medial dStr, while they elicit ionotropic glutamate responses in the lateral dStr. The DA neurons mediating these excitatory signals are in the substantia nigra (SN). Thus, SN dopamine neurons engage different receptors in different postsynaptic neurons in different dStr subregions to convey strikingly different signals.

neuroscience↗

bioRxiv2017

Dopamine neuron dependent behaviors mediated by glutamate cotransmission

Dopamine neurons in the ventral tegmental area use glutamate as a cotransmitter. To elucidate the behavioral role of the cotransmission, we targeted the glutamate-recycling enzyme glutaminase (gene GLS1). In mice with a DAT-driven conditional heterozygous (cHET) reduction of GLS1 in their dopamine neurons, dopamine neuron survival and transmission were unaffected, while glutamate cotransmission at phasic firing frequencies was reduced, enabling focusing the cotransmission. DAT GLS1 cHET mice showed normal emotional and motor behaviors, and an unaffected response to acute amphetamine. Strikingly, amphetamine sensitization was reduced and latent inhibition potentiated. These behavioral effects, also seen in global GLS1 HETs with a schizophrenia resilience phenotype, were not seen in mice with an Emx1-driven forebrain reduction affecting most brain glutamatergic neurons. Thus, a reduction in dopamine neuron glutamate cotransmission appears to mediate significant components of the GLS1 HET schizophrenia resilience phenotype, and glutamate cotransmission appears to be important in attribution of motivational salience.

neuroscience↗