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1. Changes in the Proportion of Inhibitory Interneuron Types from Sensory to Executive Areas of the Primate Neocortex: Implications for the Origins of Working Memory Representations

   https://doi.org/10.1093/cercor/bhaa056  

   Torres-Gomez, Santiago; Blonde, Jackson D; Mendoza-Halliday, Diego; Kuebler, Eric; Everest, Michelle; Wang, Xiao Jing; Inoue, Wataru; Poulter, Michael O; Martinez-Trujillo, Julio (March 2020, Cerebral Cortex)

   null (Ed.)

   Abstract Neuronal spiking activity encoding working memory (WM) is robust in primate association cortices but weak or absent in early sensory cortices. This may be linked to changes in the proportion of neuronal types across areas that influence circuits’ ability to generate recurrent excitation. We recorded neuronal activity from areas middle temporal (MT), medial superior temporal (MST), and the lateral prefrontal cortex (LPFC) of monkeys performing a WM task and classified neurons as narrow (NS) and broad spiking (BS). The ratio NS/BS decreased from MT > MST > LPFC. We analyzed the Allen Institute database of ex vivo mice/human intracellular recordings to interpret our data. Our analysis suggests that NS neurons correspond to parvalbumin (PV) or somatostatin (SST) interneurons while BS neurons are pyramidal (P) cells or vasoactive intestinal peptide (VIP) interneurons. We labeled neurons in monkey tissue sections of MT/MST and LPFC and found that the proportion of PV in cortical layers 2/3 decreased, while the proportion of CR cells increased from MT/MST to LPFC. Assuming that primate CR/CB/PV cells perform similar computations as mice VIP/SST/PV cells, our results suggest that changes in the proportion of CR and PV neurons in layers 2/3 cells may favor the emergence of activity encoding WM in association areas. 

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2. Distinct in vivo dynamics of excitatory synapses onto cortical pyramidal neurons and parvalbumin-positive interneurons

   https://doi.org/10.1016/j.celrep.2021.109972  

   Melander, Joshua B; Nayebi, Aran; Jongbloets, Bart C; Fortin, Dale A; Qin, Maozhen; Ganguli, Surya; Mao, Tianyi; Zhong, Haining (November 2021, Cell Reports)

   Cortical function relies on the balanced activation of excitatory and inhibitory neurons. However, little is known about the organization and dynamics of shaft excitatory synapses onto cortical inhibitory interneu- rons. Here, we use the excitatory postsynaptic marker PSD-95, fluorescently labeled at endogenous levels, as a proxy for excitatory synapses onto layer 2/3 pyramidal neurons and parvalbumin-positive (PV+) interneu- rons in the barrel cortex of adult mice. Longitudinal in vivo imaging under baseline conditions reveals that, although synaptic weights in both neuronal types are log-normally distributed, synapses onto PV+ neurons are less heterogeneous and more stable. Markov model analyses suggest that the synaptic weight distribu- tion is set intrinsically by ongoing cell-type-specific dynamics, and substantial changes are due to accumu- lated gradual changes. Synaptic weight dynamics are multiplicative, i.e., changes scale with weights, although PV+ synapses also exhibit an additive component. These results reveal that cell-type-specific pro- cesses govern cortical synaptic strengths and dynamics. 

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3. Creation of Neuronal Ensembles and Cell-Specific Homeostatic Plasticity through Chronic Sparse Optogenetic Stimulation

   https://doi.org/10.1523/JNEUROSCI.1104-22.2022  

   Liu, Benjamin; Seay, Michael J.; Buonomano, Dean V. (November 2022, The Journal of Neuroscience)

   Cortical computations emerge from the dynamics of neurons embedded in complex cortical circuits. Within these circuits, neuronal ensembles, which represent subnetworks with shared functional connectivity, emerge in an experience-dependent manner. Here we induced ensembles inex vivocortical circuits from mice of either sex by differentially activating subpopulations through chronic optogenetic stimulation. We observed a decrease in voltage correlation, and importantly a synaptic decoupling between the stimulated and nonstimulated populations. We also observed a decrease in firing rate during Up-states in the stimulated population. These ensemble-specific changes were accompanied by decreases in intrinsic excitability in the stimulated population, and a decrease in connectivity between stimulated and nonstimulated pyramidal neurons. By incorporating the empirically observed changes in intrinsic excitability and connectivity into a spiking neural network model, we were able to demonstrate that changes in both intrinsic excitability and connectivity accounted for the decreased firing rate, but only changes in connectivity accounted for the observed decorrelation. Our findings help ascertain the mechanisms underlying the ability of chronic patterned stimulation to create ensembles within cortical circuits and, importantly, show that while Up-states are a global network-wide phenomenon, functionally distinct ensembles can preserve their identity during Up-states through differential firing rates and correlations. SIGNIFICANCE STATEMENTThe connectivity and activity patterns of local cortical circuits are shaped by experience. This experience-dependent reorganization of cortical circuits is driven by complex interactions between different local learning rules, external input, and reciprocal feedback between many distinct brain areas. Here we used anex vivoapproach to demonstrate how simple forms of chronic external stimulation can shape local cortical circuits in terms of their correlated activity and functional connectivity. The absence of feedback between different brain areas and full control of external input allowed for a tractable system to study the underlying mechanisms and development of a computational model. Results show that differential stimulation of subpopulations of neurons significantly reshapes cortical circuits and forms subnetworks referred to as neuronal ensembles. 

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4. Ketamine disrupts naturalistic coding of working memory in primate lateral prefrontal cortex networks

   https://doi.org/10.1038/s41380-021-01082-5  

   Roussy, Megan; Luna, Rogelio; Duong, Lyndon; Corrigan, Benjamin; Gulli, Roberto A.; Nogueira, Ramon; Moreno-Bote, Rubén; Sachs, Adam J.; Palaniyappan, Lena; Martinez-Trujillo, Julio C. (May 2021, Molecular Psychiatry)

   null (Ed.)

   Abstract Ketamine is a dissociative anesthetic drug, which has more recently emerged as a rapid-acting antidepressant. When acutely administered at subanesthetic doses, ketamine causes cognitive deficits like those observed in patients with schizophrenia, including impaired working memory. Although these effects have been linked to ketamine’s action as an N-methyl-D-aspartate receptor antagonist, it is unclear how synaptic alterations translate into changes in brain microcircuit function that ultimately influence cognition. Here, we administered ketamine to rhesus monkeys during a spatial working memory task set in a naturalistic virtual environment. Ketamine induced transient working memory deficits while sparing perceptual and motor skills. Working memory deficits were accompanied by decreased responses of fast spiking inhibitory interneurons and increased responses of broad spiking excitatory neurons in the lateral prefrontal cortex. This translated into a decrease in neuronal tuning and information encoded by neuronal populations about remembered locations. Our results demonstrate that ketamine differentially affects neuronal types in the neocortex; thus, it perturbs the excitation inhibition balance within prefrontal microcircuits and ultimately leads to selective working memory deficits. 

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5. Fine Control of Sound Frequency Tuning and Frequency Discrimination Acuity by Synaptic Zinc Signaling in Mouse Auditory Cortex

   https://doi.org/10.1523/JNEUROSCI.1339-18.2018  

   Kumar, Manoj; Xiong, Shanshan; Tzounopoulos, Thanos; Anderson, Charles T. (January 2019, The Journal of Neuroscience)

   Neurons in the auditory cortex are tuned to specific ranges of sound frequencies. Although the cellular and network mechanisms underlying neuronal sound frequency selectivity are well studied and reflect the interplay of thalamocortical and intracortical excitatory inputs and further refinement by cortical inhibition, the precise synaptic signaling mechanisms remain less understood. To gain further understanding on these mechanisms and their effects on sound-driven behavior, we used in vivo imaging as well as behavioral approaches in awake and behaving female and male mice. We discovered that synaptic zinc, a modulator of neurotransmission and responsiveness to sound, sharpened the sound frequency tuning of principal and parvalbumin-expressing neurons and widened the sound frequency tuning of somatostatin-expressing inhibitory neurons in layer 2/3 of the primary auditory cortex. In the absence of cortical synaptic zinc, mice exhibited reduced acuity for detecting changes in sound frequencies. Together, our results reveal that cell-type-specific effects of zinc contribute to cortical sound frequency tuning and enhance acuity for sound frequency discrimination. SIGNIFICANCE STATEMENT Neuronal tuning to specific features of sensory stimuli is a fundamental property of cortical sensory processing that advantageously supports behavior. Despite the established roles of synaptic thalamocortical and intracortical excitation and inhibition in cortical tuning, the precise synaptic signaling mechanisms remain unknown. Here, we investigated these mechanisms in the mouse auditory cortex. We discovered a previously unknown signaling mechanism linking synaptic zinc signaling with cell-specific cortical tuning and enhancement in sound frequency discrimination acuity. Given the abundance of synaptic zinc in all sensory cortices, this newly discovered interaction between synaptic zinc and cortical tuning can provide a general mechanism for modulating neuronal stimulus specificity and sensory-driven behavior. 

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