Drug-induced change in transmitter identity is a shared mechanism generating cognitive deficits

Pratelli, Marta; Thaker, Arth; Li, Huiquan; Godavarthi, Swetha K.; Spitzer, Nicholas C.

doi:10.1101/2022.06.16.496480

Cited by 5 publications

(3 citation statements)

References 88 publications

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“…Transmitter switching may occur in a number of brain regions, such as the prefrontal cortex, where the GABA/glutamate ratio changes in response to stress ( 31 – 33 ). Transmitter switching in both the adult and the developing rodent nervous system has been linked to abnormal behavior triggered by stress ( 12 , 34 , 35 ), drugs ( 36 – 38 ), or infection ( 39 ), and linked to recovery when induced by epilepsy ( 40 ) or spinal cord injury ( 41 ).…”

Section: Discussionmentioning

confidence: 99%

Generalized fear after acute stress is caused by change in neuronal cotransmitter identity

Li,

Jiang,

Ling

et al. 2024

Science

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Overgeneralization of fear to harmless situations is a core feature of anxiety disorders resulting from acute stress, yet the mechanisms by which fear becomes generalized are poorly understood. In this study, we show that generalized fear in mice results from a transmitter switch from glutamate to γ-aminobutyric acid (GABA) in serotonergic neurons of the lateral wings of the dorsal raphe. Similar change in transmitter identity was found in the postmortem brains of individuals with posttraumatic stress disorder (PTSD). Overriding the transmitter switch in mice prevented the acquisition of generalized fear. Corticosterone release and activation of glucocorticoid receptors mediated the switch, and prompt antidepressant treatment blocked the cotransmitter switch and generalized fear. Our results provide important insight into the mechanisms involved in fear generalization.

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Section: Discussionmentioning

confidence: 99%

Generalized fear after acute stress is caused by change in neuronal cotransmitter identity

Li,

Jiang,

Ling

et al. 2024

Science

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“…107 RNAscope was performed using the probes mm-Slc17a7 in the C2 channel, and mm-Slc17a6 in the C3 channel, dyed with Opal 520 and Opal 690 in a counterbalanced manner at 1:15,000 concentration to reduce background fluorescence and allow quantitation of unsaturated, clearlydistinguishable puncta. 108 Processed RNAscope sections were then mounted with Prolong Antifade Diamond (ThermoFisher) and stored long-term at 4˚C.…”

Section: Rnascope Fluorescence In Situ Hybridizationmentioning

confidence: 99%

Control of innate olfactory valence by segregated cortical amygdala circuits

Howe,

Chan,

Lee

et al. 2024

Preprint

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SUMMARYAnimals perform innate behaviors that are stereotyped responses to specific evolutionarily relevant stimuli in the absence of prior learning or experience. These behaviors can be reduced to an axis of valence, whereby specific odors evoke approach or avoidance. The cortical amygdala (plCoA) mediates innate attraction and aversion to odor. However, little is known about how this brain area gives rise to behaviors of opposing motivational valence. Here, we sought to define the circuit features of plCoA that give rise to innate olfactory behaviors of valence. We characterized the physiology, gene expression, and projections of this structure, identifying a divergent, topographic organization that selectively controls innate attraction and avoidance to odor. First, we examined odor-evoked responses in these areas and found sparse encoding of odor identity, but not valence. We next considered a topographic organization and found that optogenetic stimulation of the anterior and posterior domains of plCoA elicits attraction and avoidance, respectively, suggesting a functional axis for valence. Using single cell and spatial RNA sequencing, we identified the molecular cell types in plCoA, revealing an anteroposterior gradient in cell types, whereby anterior glutamatergic neurons preferentially expressSlc17a6and posterior neurons expressSlc17a7. Activation of these respective cell types recapitulates appetitive and aversive valence behaviors, and chemogenetic inhibition reveals partial necessity for valence responses to innate appetitive or aversive odors. Finally, we identified topographically organized circuits defined by projections, whereby anterior neurons preferentially project to medial amygdala, and posterior neurons preferentially project to nucleus accumbens, which are respectively sufficient and necessary for innate negative and positive olfactory valence. Together, these data advance our understanding of how the olfactory system generates stereotypic, hardwired attraction and avoidance, and supports a model whereby distinct, topographically distributed plCoA populations direct innate olfactory valence responses by signaling to divergent valence-specific targets, linking upstream olfactory identity to downstream valence behaviors, through a population code. This represents a novel circuit motif in which valence encoding is represented not by the firing properties of individual neurons, but by population level identity encoding that is routed through divergent targets to mediate distinct valence.

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“…Preventing these neurons from gaining GABA prevents the appearance of drug-induced deficits in the novel object recognition test and spontaneous alternation task, demonstrating a causal link between the transmitter switch and the cognitive deficits. Interestingly, chemogenetic stimulation of parvalbumin-positive inhibitory interneurons that innervate pyramidal neurons, either during drug exposure, or later after the transmitters have switched, suppresses pyramidal neuron hyperactivity and prevents, or reverses, the appearance of both the switch and the cognitive deficits (Pratelli & Spitzer, 2021).…”

Section: Current Researchmentioning

confidence: 99%

Nicholas C. Spitzer

2022

The History of Neuroscience in Autobiography, Volume 12

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Nick Spitzer carried out a sustained line of research originating in studies of the development of neuronal excitability. This led to the discovery, in the embryonic amphibian nervous system, of calcium-dependent action potentials that generate transient elevations of intracellular calcium before the action potentials achieve classical sodium-dependence. He found that changes in this calcium-dependent electrical activity cause neurotransmitter switching, which is associated with matching changes in postsynaptic receptors. He subsequently discovered that changes in electrical activity also drive transmitter switching and receptor matching in the adult mammalian brain. Transmitter switching often switches the sign of the synapse and leads to changes in behavior that can be detrimental or beneficial. These findings identified a novel form of plasticity, distinct from changes in synaptic weight and synapse number, and overturned the long-held view that the choice of transmitter is irreversibly specified by cell identity at an early stage of development.

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Drug-induced change in transmitter identity is a shared mechanism generating cognitive deficits

Cited by 5 publications

References 88 publications

Generalized fear after acute stress is caused by change in neuronal cotransmitter identity

Generalized fear after acute stress is caused by change in neuronal cotransmitter identity

Control of innate olfactory valence by segregated cortical amygdala circuits

Nicholas C. Spitzer

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