Chemogenetic stimulation of oxytocinergic neurons dynamically modulates fMRI connectivity
C. Montani1, *A. Hayward1, D. Gutierrez-Barragan1, G. Morelli2, F. G. Alvino1, L. Coletta1,3, A. Galbusera1, M. Pasqualetti4, L. Cancedda2, A. Gozzi1
1) Functional Neuroimaging Lab., Inst. Italiano di Tecnologia, Rovereto, Italy; 2) Brain Develop. and Dis. Lab., Inst. Italiano di Tecnologia, Genoa, Italy; 3) CIMeC - Ctr. for Mind/Brain Sci., Univ. of Trento, Rovereto, Italy; 4) Unit of Cell and Developmental Biology, Dept. of Biol., Univ. of Pisa, Pisa, Italy
Presentation Number: 141.06
Presentation Time: Sun., Nov. 13, 2022 9:00 AM - 10:00 AM
Posterboard Number: Z11
Oxytocin (OXT) is a key modulator of complex socio-affective behaviors. However, the brain-wide networks endogenously modulated by OXT remain poorly understood.
Here, we combine chemogenetics and fMRI to map the topography and dynamics of brain networks engaged by endogenously-released OXT in the mammalian brain. To remotely stimulate endogenous OXT release, we crossed mice harboring a double-floxed DREADD activator hM3Dq with OXT-specific Cre-recombinase mice, leading to cell-type specific expression of hM3Dq in OXT-producing neurons. Stimulation of DREADD receptors with the selective JHU37160 actuator in OXT-hM3Dq mice produced physiologically-relevant release of OXT, an effect that was associated with increased grooming behavior as previously reported.
fMRI mapping of OXT-evoked activity in OXT-hM3Dq (n=20) vs. control (n=21) mice revealed sustained fMRI (cerebral blood volume) activation of parietal cortical areas, hypothalamus and dorsal hippocampal regions. These effects were associated with a dramatic reconfiguration of fMRI connectivity as assessed with resting state fMRI. Specifically, chemogenetic stimulation of OXT-producing neurons robustly increased functional connectivity between hypothalamic regions and prefrontal areas, and by inverse coupling between insular and amygdala regions of the rodent salience network, and between the hippocampus and fronto-cortical areas. Notably, these changes were paralleled by a distinct reorganization of the temporal structure of rsfMRI connectivity, with a robustly increased occurrence of dynamics states encompassing the rodent salience network, which were configured as network attractors.
Taken together, these results show that endogenous OXT can rapidly and robustly alter interareal communication between key components of the social brain via temporal re-organization of fMRI dynamics.
Evolutionarily conserved fMRI coactivation dynamics in the human, macaque and mouse brain
*D. Gutierrez-Barragan1, J. S. B. Ramirez2, S. Panzeri3, T. Xu2, A. Gozzi1
1) Functional Neuroimaging Lab., Inst. Italiano di Tecnologia, CNCS, Rovereto, Italy; 2) Ctr. for the Developing Brain, Child Mind Inst., New York, NY; 3) Ctr. for Mol. Neurobiology, Dept. of Excellence for Neural Information Processing, Univ. Hamburg, Hamburg, Germany
Presentation Number: 141.19
Presentation Time: Sun., Nov. 13, 2022 10:00 AM - 11:00 AM
Posterboard Number: AA9
Evolutionarily relevant networks of spontaneous brain activity have been consistently mapped in humans, primates and rodents using resting-state fMRI (rsfMRI). It is however unclear whether the dynamic rules that govern rsfMRI network dynamics are species-invariant, or if they instead have evolved across the phylogenetic tree. Here, we used frame-wise clustering of rsfMRI timeseries acquired in awake mice, macaques, and humans, to map and compare the topography and dynamic properties of rsfMRI co-activation patterns (CAPs) across species.
We report that rsfMRI dynamics in the mammalian brain is characterized by recurrent transitions between fluctuating BOLD co-activation patterns (CAPs), whose topography and dynamics follow evolutionarily-conserved principles. Specifically, in all species rsfMRI activity could be reliably partitioned in a small number (k= 6, mouse, n=51; k=8, macaque, n=8 x 2 sessions, k = 8, human, n=10 x 5 sessions) of stable and reproducible CAPs across independent datasets/sessions, explaining a substantial fraction of rsfMRI variance (R2>0.6, all species). Moreover, mouse, macaque and human CAPs could be paired into spatially opposing topographies, indicative of peaks and throughs of fluctuating fMRI network activity. Spectral analyses revealed that CAPs fluctuate with centered power in the infraslow range (0.01-0.04Hz), and that CAPs exhibited preferential occurrence within Global fMRI Signal (GS) cycle that in all species, indicative of species-invariant relationship between CAP emergence and fMRI global signal cycles. Evolutionarily-conserved CAP topographies were also apparent, with evidence of a competing engagement of default-mode network (DMN) and somatosensory regions (CAPs 1-2), as well as the presence of pan-cortical patterns of fMRI coactivation (CAPs 3-4) in all species. In keeping with cortical expansion along the phylogenetic tree, one CAP pair was instead reliably identified only in human and macaque, exhibiting primate-specific features in high-order regions of dorsal-attention and executive-networks. Taken together, our results reveal a set of fundamental, evolutionarily-conserved principles underlying rsfMRI network dynamics in the awake mammalian brain.
Cortical excitatory/inhibitory balance critically controls brain-wide fMRI
*D. Sastre Yagüe1,3, F. Rocchi1,3, A. Stuefer1,3, S. Noei2,3, L. Coletta1, F. Alvino1, A. Galbusera1, S. Panzeri4, A. Gozzi1;
1) Functional Neuroimaging Lab., 2) CNCS, Inst. Italiano di Tecnologia (IIT), Rovereto, Italy; 3) Cimec, Univ. of Trento, Rovereto, Italy; 4) Ctr. for Mol. Neurobio. Hamburg (ZMNH), Hamburg, Germany
Presentation Number: 141.12
Presentation Time: Sun., Nov. 13, 2022 11:00 AM - 12:00 PM
Posterboard Number: AA2
Resting-state fMRI (rsfMRI) is widely used to map intrinsic brain network organization in the healthy, as well as in psychiatric and neurological disorders, where evidence of disrupted or abnormal rsfMRI functional coupling has been largely documented. However, the neural underpinnings and dynamic rules governing brain-wide rsfMRI coupling remain unclear. Neocortical excitatory/inhibitory (E/I) balance critically affects local and long-range information processing and can conceivably bias brain-wide network coupling as measured with rsfMRI. This notion would be consistent with the emerging evidence of neocortical imbalance and altered interareal communication in multiple brain disorders such as Autism Spectrum Disorder or Schizophrenia. Here we combine chemogenetic manipulations, rsfMRI, electrophysiology and behavioral measurements to causally probe how neocortical excitatory-inhibitory balance affects brain-wide fMRI and neural coupling in the mouse brain. We used DREADD-based chemogenetics to remotely alter E/I balance in the mouse prefrontal cortex (PFC) by increasing pyramidal neuron excitability, or by reducing the activity of subclasses of inhibitory interneurons. For each of the employed manipulations, we recorded rsfMRI network activity, and the underlying neural rhythm via in-vivo multielectrode electrophysiology before and after CNO administration. We found that increasing PFC excitability via DREADD activation of CamkII-expressing pyramidal neurons dramatically desynchronized brain-wide rsfMRI functional connectivity in the mouse default network, an effect that was associated with increased gamma activity and reduced low frequency interareal coherence. Notably, analogous connectivity and neural desynchronization was observed upon chemogenetic inhibition of fast-spiking parvalbumin positive interneurons, but not somatostatin-positive cells. Importantly, all connectivity-affecting perturbations were associated with socio-communicative deficits as assessed in a three-chamber sociability test, hence underscoring the behavioral relevance of the employed manipulations. Our results show that excitatory/inhibitory balance critically biases brain-wide fMRI coupling and point at a possible unifying mechanistic link between E/I imbalance and connectivity disruption in brain disorders.