Biology subjects

Malfatti, T.

Publications and source records attributed to Malfatti, T..

7 recordsLinked to original sources

bioRxiv2026

Layer 5 Martinotti and pyramidal neurons encode spatial information in the primary motor cortex

Mammals rely on external sensory cues and internal bodily signals to create a precise spatial awareness. The motor cortex is essential for this process, integrating proprioceptive and spatial information. Here, we investigate how layer 5 martinotti (M2) interneurons and pyramidal cells contribute to spatial processing in primary motor cortex (M1). Using miniscopes in freely moving mice expressing CaMKIIa-GCaMP8f or DIO-GCaMP8f in Chrna2-Cre+ mice, we recorded activity from both cell types. We found that both M2 and pyramidal cells are tuned to place, head direction, and grid fields, with distinct characteristics. Notably, both cell types exhibit an overrepresentation of co-tuned place- and head-direction responses compared to chance. Moverover, pyramidal head direction-tuned cells show sharper tuning than M2 head direction-tuned cells. Further, place-tuned M2 cells are more active, whereas pyramidal place-tuned cells showed reduced activity compared to non-place-tuned ones. Additionally, both cell types exhibit lower activity in head-direction-tuned compared to non-head direction-tuned cells. These findings suggest that distinct neural coding strategies are employed by different cell types within the M1 for processing spatial information, highlighting the complex neural mechanisms underlying spatial cognition.

neuroscience↗

bioRxiv2025

Y-maze and Vertical Pole Performance Correlate with Fine Motor Learning in Mice

The relationships between distinct abilities and their interdependencies during memory tasks and motor learning activities are not clear. An important question is whether being proficient in memory or motor learning tasks also translates into better performance in another, similar task - reflecting potential generalization of motor learning abilities. To investigate the correlation between memory performance and motor learning, we used a combination of behavioral tasks that assess general exploratory behavior, declarative memory, and fine motor learning in female mice. For the exploratory behavior, we used the open field task, and assessed declarative memory using the novel object recognition and Y-maze. Motor performance and learning was assessed through the vertical pole and pellet reaching task. We found a positive correlation between the Y-maze and the pellet reaching task performance, where a higher exploration rate indicated a higher success ratio in the pellet reaching task. Further, leave-one-out cross-validation prediction analysis show that Y-maze performance is a robust predictor of pellet reaching performance, showing that mice pellet reaching performance can reliably be predicted from Y-maze performance. These results can be used to conduct a pre-study for challenging motor tasks that include pre-behavioral procedures on mice. Our study shows that performance in the Y-maze predicts pellet reaching performance, indicating that these tasks can be used as pre-screening for motor learning performance and activity.

neuroscience↗

bioRxiv2024

Layer 5 Martinotti cell activation reduces pyramidal cell population plasticity and improves fine motor function

During motor activity and motor learning, pyramidal cells in the motor cortex receive inputs from local interneurons as well as deeper structures. Layer 5 pyramidal cells in the primary motor cortex then feed commands to spinal circuits for motor execution. The genetic ablation of layer 5 Chrna2 Martinotti cells, which selectively target pyramidal tract pyramidal cells, resulted in disturbed fine motor functions. Using calcium imaging combined with chemogenetics, we show that activation of layer 5 Chrna2 Martinotti cells during training increases pyramidal cell tuning, changes responses temporal patterns and decreases assembly reconfiguration, while not affecting motor learning success rates. However, in mice that had already learned a reach-and-grasp (prehension) task, Chrna2 Martinotti cell activation resulted in improved prehension and increased power in low theta and high gamma bands of local field potentials in the motor cortex. This work indicates that activation of Chrna2 Martinotti cells reduces pyramidal cell assembly plasticity during learning, possibly facilitating already acquired motor skills.

neuroscience↗

bioRxiv2023

Unraveling the role of Slc10a4 in auditory processing and sensory motor gating: implications for neuropsychiatric disorders?

BackgroundPsychiatric disorders, such as schizophrenia, are complex and challenging to study, partly due to the lack of suitable animal models. However, the absence of the Slc10a4 gene, which codes for a monoaminergic and cholinergic associated vesicular transporter protein, in knockout mice (Slc10a4 -/-), leads to the accumulation of extracellular dopamine. This makes them a potential animal model for schizophrenia, a disorder known to be associated with altered dopamine signaling in the brain. MethodsThe locomotion, auditory sensory filtering and prepulse inhibition (PPI) of Slc10a4 -/- mice were quantified and compared to wildtype (WT) littermates. Intrahippocampal electrodes were used to record auditory event-related potentials (aERPs) for quantifying sensory filtering in response to paired-clicks. The channel above aERPs phase reversal was chosen for reliably comparing results between animals, and aERPs amplitude and latency of click responses were quantified. WT and Slc10a4 -/- mice were also administered subanesthetic doses of ketamine to provoke psychomimetic behavior. ResultsBaseline locomotion during auditory stimulation was similar between Slc10a4 -/- mice and WT littermates. In WT animals, normal auditory gating was observed after i.p saline injections, and it was maintained under the influence of 5 mg/kg ketamine, but disrupted by 20 mg/kg ketamine. On the other hand, Slc10a4 -/- mice did not show significant differences between N40 S1 and S2 amplitude responses in saline or low dose ketamine treatment. Auditory gating was considered preserved since the second N40 peak was consistently suppressed, but with increased latency. The P80 component showed higher amplitude, with shorter S2 latency under saline and 5 mg/kg ketamine treatment in Slc10a4 -/- mice, which was not observed in WT littermates. Prepulse inhibition was also decreased in Slc10a4 -/- mice when the longer interstimulus interval of 100 ms was applied, compared to WT littermates. ConclusionThe Slc10a4 -/- mice responses indicate that cholinergic and monoaminergic systems participate in the PPI magnitude, in the temporal coding (response latency) of the auditory sensory gating component N40, and in the amplitude of aERPs P80 component. These results suggest that Slc10a4 -/- mice can be considered as potential models for neuropsychiatric conditions.

neuroscience↗

bioRxiv2022

Alterations of auditory sensory gating in mice with noise-induced tinnitus treated with nicotine and cannabis extract

Tinnitus is a phantom sound perception affecting both auditory and limbic structures. The mechanisms of tinnitus remain unclear and it is debatable whether tinnitus alters attention to sound and the ability to inhibit repetitive sounds, a phenomenon also known as auditory gating. Here we investigate if noise exposure interferes with auditory gating and whether natural extracts of cannabis or nicotine could improve auditory pre-attentional processing in noise-exposed mice. We used 22 male C57BL/6J mice divided into noise-exposed (exposed to a 9-11 kHz narrow band noise for 1 hour) and sham (no sound during noise exposure) groups. Hearing thresholds were measured using auditory brainstem responses, and tinnitus-like behavior was assessed using Gap prepulse inhibition of acoustic startle. After noise exposure, mice were implanted with multi-electrodes in the dorsal hippocampus to assess auditory event-related potentials in response to paired clicks. The results showed that mice with tinnitus-like behavior displayed auditory gating of repetitive clicks, but with larger amplitudes and longer latencies of the N40 component of the aERP waveform. The combination of cannabis extract and nicotine improved auditory gating ratio in noise-exposed mice without permanent hearing threshold shifts. Lastly, the longer latency of the N40 component appears due to an increased sensitivity to cannabis extract in noise-exposed mice compared to sham mice. The study suggests that the altered central plasticity in tinnitus is more sensitive to the combined actions on the cholinergic and the endocannabinoid systems. Overall, the findings contribute to a better understanding of pharmacological modulation of auditory sensory gating.

neuroscience↗

bioRxiv2021

Activity of CaMKIIa+ dorsal cochlear nucleus neurons are crucial for tinnitus perception but not for tinnitus induction

The dorsal cochlear nucleus (DCN) is a region known to integrate somatosensory and auditory inputs and is identified as a potential key structure in the generation of phantom sound perception, especially noise-induced tinnitus. Yet, how altered homeostatic plasticity of the DCN induces and maintains the sensation of tinnitus is not clear. Here, we chemogenetically decrease activity of a subgroup of DCN neurons, Ca2+/Calmodulin kinase 2 (CaMKII) positive DCN neurons, using Gi-coupled human M4 Designer Receptors Exclusively Activated by Designer Drugs (hM4Di DREADDs), to investigate their role in noise-induced tinnitus. Mice were exposed to loud noise (9-11kHz, 90dBSPL, 1h, followed by 2h of silence) and auditory brainstem responses (ABRs) and gap prepulse inhibition of acoustic startle (GPIAS) were recorded two days before and two weeks after noise exposure to identify animals with a significantly decreased inhibition of startle, indicating tinnitus but without permanent hearing loss. Neuronal activity of CaMKII+ neurons expressing hM4Di in the DCN was lowered by administration of clozapine-N-oxide (CNO). We found that acutely decreasing firing rate of CaMKII+ DCN units decrease tinnitus-like responses (p = 0.038, n = 11 mice), compared to the control group that showed no improvement in GPIAS (control virus; CaMKII-YFP + CNO, p = 0.696, n = 7 mice). Extracellular recordings confirmed CNO to decrease unit firing frequency of CaMKII-hM4Di+ mice and alter best frequency and tuning width of response to sound. However, these effects were not seen if CNO had been previously administered during the noise exposure (n = 6 experimental and 6 control mice). Our results suggest that CaMKII-hM4Di positive cells in the DCN are not crucial for tinnitus induction but play a significant role in maintaining tinnitus perception in mice.

neuroscience↗

bioRxiv2020

Using cortical neuron markers to target cells in the dorsal cochlear nucleus

The dorsal cochlear nucleus (DCN) is the first auditory region that integrates somatosensory and auditory inputs. The region is of particular interest for auditory research due to the large incidence of somatic tinnitus and increased aberrant activity in other forms of tinnitus. Yet, the lack of useful genetic markers for in vivo manipulations hinders the elucidation of the DCN contribution to tinnitus pathophysiology. In this work, we assessed whether adeno-associated viral vectors (AAV) containing the calcium/calmodulin-dependent protein kinase 2 alpha (CaMKII) promoter and our mouse line of nicotinic acetylcholine receptor alpha 2 subunit (Chrna2)-Cre can be used to target specific DCN populations. The CaMKII promoter is usually applied in studies of principal neurons of neo and paleocortex while Chrna2-cre mice express Cre recombinase in cortical dendrite inhibiting interneurons. We found that CaMKII cannot be used to specifically target excitatory fusiform DCN neurons. EYFP expression driven by the CaMKII promoter was stronger in the fusiform layer but labelled cells showed a diverse morphology indicating that they belong to different classes of DCN neurons. Light stimulation after driving Channelrhodopsin2 (ChR2) by the CaMKII promoter generated spikes in some units but firing rate decreased when light stimulation coincide with sound presentation. Expression and activation of eArch3.0 (CaMKII driven) in the DCN produced spike inhibition in some units but, most importantly, sound-driven spikes were delayed by concomitant light stimulation. We explored the existence of Cre+ cells in the DCN of Chrna2-Cre mice by hydrogel embedding technique (CLARITY). There were almost no Cre+ cell bodies in the DCN; however, we observed profuse projections arising from the ventral cochlear nucleus (VCN). Anterograde labeling Cre dependent AAV injected in the VCN revealed two main projections: one arising in the ipsilateral superior olive and the contralateral medial nucleus of the trapezoid body (bushy cells) and a second bundle terminating in the DCN, suggesting the latter to be excitatory Chrna2+ T-stellate cells). Stimulating ChR2 expressing terminals (light applied on the DCN) of VCN Chrna2+ cells increased firing of sound responding and nonresponding DCN units. This work shows that molecular tools intensively used in cortical studies may be useful for manipulating the DCN especially in tinnitus studies.

neuroscience↗