Biology subjects

Federman, N.

Publications and source records attributed to Federman, N..

5 recordsLinked to original sources

bioRxiv2024

Lateral entorhinal cortex afferents reconfigure the activity in piriform cortex circuits

Odours are key signals for guiding spatial behaviours such as foraging and navigation in rodents. It has recently been found that odour representations in the piriform cortex (PCx) can also contain information about their spatial context. However, the precise origins of this information within the brain and its subsequent integration into the microcircuitry of the PCx remains unknown. In this study, we focus on the lateral entorhinal cortex (LEC) as a candidate for carrying spatial contextual information to the PCx, to investigate how it affects the PCx microcircuit and its response to olfactory inputs. Utilising mice brain slices, we performed patch clamp recordings targeting both superficial (SP) and deep (DP) pyramidal neurons, as well as parvalbumin (PV) and somatostatin (SOM) inhibitory interneurons. Concurrently, we optogenetically stimulated excitatory LEC projections to study their impact on PCx activity. We found that LEC inputs are heterogeneously distributed in the PCx microcircuit, evoking larger excitatory currents in SP and PV neurons compared to DP and SOM neurons, respectively, due to their higher monosynaptic connectivity. Moreover, LEC inputs exert a differential effect on the inhibitory circuits, activating PV while suppressing SOM interneurons. We further studied the interaction among LEC inputs and the sensory afferent signals originating from the lateral olfactory tract (LOT) onto the PCx. Our findings demonstrated that both SP and DP neurons show a general increase in their spiking response when LEC and LOT are simultaneously activated. Notably, DP neurons exhibit a sharpening of their response attributable to LEC-induced inhibition that effectively suppresses the delayed spikes evoked by LOT stimulation. These observations suggest a regulatory mechanism whereby LEC inputs inhibit recurrent activity by activating PV interneurons. Our results show that LEC afferents reconfigure PCx activity and contribute to the understanding of how odour objects are formed within the PCx integrating both olfactory and contextual information. Significant statementPrimary sensory cortices are more complex than initially thought, encoding movement-related information, as well as spatial maps of animal location. The primary olfactory cortex, the piriform cortex (PCx), not only responds to the presence of odours, but to other non-olfactory signals like the spatial context in which odours are presented. The source of the contextual modulation is not known. In this work, we studied the modulation of PCx neurons by afferents arriving from the lateral entorhinal cortex (LEC), an area related to spatial representation. By the use of optogenetic to activate LEC inputs we found that its activation recruits excitatory and inhibitory circuits in PCx. The interaction of LEC inputs with afferents carrying odour information arriving from the lateral olfactory tract (LOT) resulted in a sharpening PCx principal neurons response to LOT, by a reduction in recurrent activity through PV interneurons. This circuital reorganisation of activity in PCx by LEC afferents could be an important mechanism to switch responses to be favouring dominance of the LOT pathway over the recurrent pathway. These results shed light on the understanding of how contextual aspects of animal experience, in which LEC is involved, can influence odour processing potentially leading to a richer representation of odour objects.

neuroscience↗

bioRxiv2023

Acquisition of non-olfactory encoding improves odour discrimination in olfactory cortex

Primary sensory cortices, initially considered elementary encoders of physicochemical attributes of environmental stimuli, are now known to be modulated by other aspects of experience, such as attentional state and internal expectations 1-3, movement-related signals 4-7 and spatial information 2, 8, 9. However, the specific role of these signals in cortical sensory processing is not fully understood 10. Here we reveal multiple and diverse non-olfactory responses in the primary olfactory (piriform) cortex (PCx), which dynamically enhance PCx odour discrimination according to behavioural demands. We designed a behavioural task using a virtual reality environment and performed recordings in PCx neurons. In this task, mice were trained to associate specific odours with visual contexts in order to receive a reward. We found that learning shifts PCx activity from encoding solely odour identity to a more complex regime. In this regime, positional, contextual, and associative responses emerge on odour-responsive neurons that thus become mixed-selective. Contextual information is sustained in PCx activity of expert animals, specifically when visual context identity is needed to solve the task. After learning, odours are better decoded from PCx activity when mice are engaged in the task and when odours are presented within a rewarded context. This enhancement of PCx olfactory processing is reliant on the acquired mixed-selectivity. Thus, the integration of extra-sensory inputs within primary sensory cortices can encode the behavioural relevance of encountered stimuli while improving sensory processing.

neuroscience↗

bioRxiv2023

The landscape of drug sensitivity and resistance in sarcoma

Sarcomas are a family of rare malignancies composed of over 100 distinct histological subtypes. The rarity of sarcoma poses significant challenges in conducting clinical trials to identify effective therapies, to the point that many rarer subtypes of sarcoma do not have standard-of-care treatment. Even for established regimens, there can be substantial heterogeneity in responses. Overall, novel, personalized approaches for identifying effective treatments are needed to improve patient out-comes. Patient-derived tumor organoids (PDTOs) are clinically relevant models representative of the physiological behavior of tumors across an array of malignancies. Here, we use PDTOs as a tool to better understand the biology of individual tumors and characterize the landscape of drug resistance and sensitivity in sarcoma. We collected n=194 specimens from n=126 sarcoma patients, spanning 24 distinct subtypes. We characterized PDTOs established from over 120 biopsy, resection, and metastasectomy samples. We leveraged our organoid high-throughput drug screening pipeline to test the efficacy of chemotherapeutics, targeted agents, and combination therapies, with results available within a week from tissue collection. Sarcoma PDTOs showed patient-specific growth characteristics and subtype-specific histopathology. Organoid sensitivity correlated with diagnostic subtype, patient age at diagnosis, lesion type, prior treatment history, and disease trajectory for a subset of the compounds screened. We found 90 biological pathways that were implicated in response to treatment of bone and soft tissue sarcoma organoids. By comparing functional responses of organoids and genetic features of the tumors, we show how PDTO drug screening can provide an orthogonal set of information to facilitate optimal drug selection, avoid ineffective therapies, and mirror patient outcomes in sarcoma. In aggregate, we were able to identify at least one effective FDA-approved or NCCN-recommended regimen for 59% of the specimens tested, providing an estimate of the proportion of immediately actionable information identified through our pipeline. HighlightsO_LIStandardized organoid culture preserve unique sarcoma histopathological features C_LIO_LIDrug screening on patient-derived sarcoma organoids provides sensitivity information that correlates with clinical features and yields actionable information for treatment guidance C_LIO_LIHigh-throughput screenings provide orthogonal information to genetic sequencing C_LIO_LISarcoma organoid response to treatment correlates with patient response to therapy C_LIO_LILarge scale, functional precision medicine programs for rare cancers are feasible within a single institution C_LI

cancer biology↗

bioRxiv2021

Personalized chordoma organoids for drug discovery studies

Chordomas are rare tumors of notochordal origin, most commonly arising in the sacrum or skull base. Primary treatment of chordoma is surgery, however complete resection is not always feasible due to their anatomic location, and recurrence rates remain high. Chordomas are considered insensitive to conventional chemotherapy, and their rarity complicates running timely and adequately powered trials to identify effective regimens. Therefore, there is a need for discovery of novel therapeutic approaches. Drug discovery efforts in chordoma have been mostly limited to cell line models. Patient-derived organoids can accelerate drug discovery studies and predict patient responses to therapy. In this proof-of-concept study, we successfully established organoids from seven chordoma tumor samples obtained from five patients presenting with tumors in different sites and stages of disease. The organoids recapitulated features of the original parent tumors and inter-as well as intra-patient heterogeneity. High-throughput screenings performed on the organoids highlighted targeted agents such as PI3K/mTOR, EGFR, and JAK2/STAT3 inhibitors among the most effective molecules. Pathway analysis underscored how the NF-kB and IGF-1R pathways are sensitive to perturbations and potential targets to pursue for combination therapy of chordoma.

cancer biology↗

bioRxiv2019

Cholinergic modulation of dentate gyrus processing through dynamic reconfiguration of inhibitory circuits

The dentate gyrus (DG) of the hippocampus plays a key role in memory formation and it is known to be modulated by septal projections. By performing electrophysiology and optogenetics we evaluated the role of cholinergic modulation in the processing of afferent inputs in the DG. We showed that mature granule cells (GCs), but not adult-born immature neurons, have increased responses to afferent perforant path stimuli upon cholinergic modulation. This is due to a highly precise reconfiguration of inhibitory circuits, differentially affecting Parvalbumin and Somatostatin interneurons, resulting in a nicotinic-dependent perisomatic disinhibition of GCs. This circuit reorganization provides a mechanism by which mature GCs could escape the strong inhibition they receive, creating a window of opportunity for plasticity. Indeed, coincident activation of perforant path inputs with optogenetic release of acetylcholine produced a long-term potentiated response in GCs, essential for memory formation.

neuroscience↗