Biology subjects

Penzo, M. A.

Publications and source records attributed to Penzo, M. A..

4 recordsLinked to original sources

bioRxiv2025

A synaptic mechanism for encoding the learned value of action-derived safety

Motivated behavior is often framed in terms of biologically grounded outcomes, such as food or threat. Yet many motivated actions, like the pursuit of safety or agency, depend on outcomes that lack explicit sensory value and must instead be inferred from experience. Here, we identify a thalamostriatal circuit mechanism by which such internally constructed outcomes acquire motivational value. In mice performing an active avoidance task, neurons in the paraventricular thalamus (PVT) projecting to the nucleus accumbens (NAc) develop a safety-encoding signal that emerges following successful avoidance. This signal is experience-dependent and value-sensitive, diminishing upon devaluation of the instrumental contingency. Selective silencing of the PVT[->]NAc projection at safety onset disrupts avoidance persistence without impairing action-outcome learning, as confirmed by computational modeling of value updating based on prediction error. Mechanistically, PVT input recruits cholinergic interneurons (CINs) to modulate dopamine release and this influence depends on synaptic potentiation mediated by GluA2-lacking AMPA receptor insertion at PVT-CIN synapses. Disrupting this plasticity selectively impairs the avoidance response by blunting the motivational value of safety without affecting acquisition. These findings reveal how thalamic circuits assign value to abstract, internal outcomes, providing a framework for understanding how goals like safety are inferred, stabilized, and rendered behaviorally effective.

neuroscience↗

bioRxiv2024

A conserved cell-type gradient across the human mediodorsal and paraventricular thalamus

The mediodorsal thalamus (MD) and adjacent midline nuclei are important for cognition and mental illness, but their cellular composition is not well defined. Using single-nucleus and spatial transcriptomics, we identified a conserved excitatory neuron gradient, with distinct spatial mapping of individual clusters. One end of the gradient was expanded in human MD compared to mice, which may be related to the expansion of granular prefrontal cortex in hominids. Moreover, neurons preferentially mapping onto the parvocellular division MD were associated with genetic risk for schizophrenia and bipolar disorder. Midbrain-derived inhibitory interneurons were enriched in human MD and implicated in genetic risk for major depressive disorder.

neuroscience↗

bioRxiv2022

Molecular and spatial profiling of the paraventricular nucleus of the thalamus

The paraventricular nucleus of the thalamus (PVT) is known to regulate various cognitive and behavioral processes. However, while functional diversity among PVT circuits has often been linked to cellular differences, the molecular identity and spatial distribution of PVT cell types remains unclear. To address this gap, here we used single nucleus RNA sequencing (snRNA-seq) and identified five molecularly distinct PVT neuronal subtypes. Additionally, multiplex fluorescent in situ hybridization of top marker genes revealed that PVT subtypes are organized by a combination of previously unidentified molecular gradients. Lastly, comparing our dataset with a recently published single-cell sequencing atlas of thalamus yielded novel insight into the PVTs connectivity with cortex, including unexpected innervation of auditory and visual areas. This comparison also revealed that our data contains a largely non-overlapping transcriptomic map of multiple midline thalamic nuclei. Collectively, our findings uncover previously unknown features of the molecular diversity and anatomical organization of the PVT and provide a valuable resource for future investigations.

neuroscience↗

bioRxiv2017

An insula-central amygdala circuit for behavioral inhibition

Predicting which substances are suitable for consumption during foraging is critical for animals to survive. While food-seeking behavior is extensively studied, the neural circuit mechanisms underlying avoidance of potentially poisonous substances remain poorly understood. Here we examined the role of the insular cortex (IC) to central amygdala (CeA) circuit in the establishment of such avoidance behavior. Using anatomic tracing approaches combined with optogenetics-assisted circuit mapping, we found that the gustatory region of the IC sends direct excitatory projections to the lateral division of the CeA (CeL), making monosynaptic excitatory connections with distinct populations of CeL neurons. Specific inhibition of neurotransmitter release from the CeL-projecting IC neurons prevented mice from acquiring the \"no-go\" response, while leaving the \"go\" response largely unaffected in a tastant (sucrose/quinine)-reinforced \"go/no-go\" task. Furthermore, selective activation of the IC-CeL pathway with optogenetics drove unconditioned lick suppression in thirsty animals, induced aversive responses, and was sufficient to instruct conditioned action suppression in response to a cue predicting the optogenetic activation. These results indicate that activity in the IC-CeL circuit is necessary for establishing anticipatory avoidance responses to an aversive tastant, and is also sufficient to drive learning of such anticipatory avoidance. This function of the IC-CeL circuit is likely important for guiding avoidance of substances with unpleasant tastes during foraging in order to minimize the chance of being poisoned.\n\nSignificance StatementThe ability to predict which substances are suitable for consumption is critical for survival. Here we found that activity in the insular cortex (IC) to central amygdala (CeA) circuit is necessary for establishing avoidance responses to an unpleasant tastant, and is also sufficient to drive learning of such avoidance responses. These results suggest that the IC-CeA circuit is critical for behavioral inhibition in anticipation of potentially poisonous substances during foraging.

neuroscience↗