Functional organization of the midbrain periaqueductal gray for regulating aversive memory formation

AbstractInnately aversive experiences produce rapid defensive responses and powerful emotional memories. The midbrain periaqueductal gray (PAG) drives defensive behaviors through projections to brainstem motor control centers, but the PAG has also been implicated in aversive learning, receives information from aversive-signaling sensory systems and sends ascending projections to the thalamus as well as other forebrain structures which could control learning and memory. Here we sought to identify PAG subregions and cell types which instruct memory formation in response to aversive events. We found that optogenetic inhibition of neurons in the dorsolateral subregion of the PAG (dlPAG), but not the ventrolateral PAG (vlPAG), during an aversive event reduced memory formation. Furthermore, inhibition of a specific population of thalamus projecting dlPAG neurons projecting to the anterior paraventricular thalamus (aPVT) reduced aversive learning, but had no effect on the expression of previously learned defensive behaviors. By contrast, inactivation of dlPAG neurons which project to the posterior PVT (pPVT) or centromedial intralaminar thalamic nucleus (CM) had no effect on learning. These results reveal specific subregions and cell types within PAG responsible for its learning related functions.

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Brief optogenetic inhibition of rat lateral or ventrolateral periaqueductal gray augments the acquisition of Pavlovian fear conditioning

10.1101/191841 ◽

2017 ◽

Author(s):

Neda Assareh ◽

Elena E. Bagley ◽

Pascal Carrive ◽

Gavan P. McNally

Keyword(s):

Fear Conditioning ◽

Viral Vectors ◽

Strong Support ◽

Periaqueductal Gray ◽

Fear Learning ◽

Defensive Responses ◽

Defensive Behaviors ◽

The Relationship ◽

Exact Timing

AbstractThe midbrain periaqueductal gray (PAG) coordinates the expression and topography of defensive behaviors to threat and also plays an important role in Pavlovian fear learning itself. Whereas the role of PAG in expression of defensive behavior is well understood, the relationship between activity of PAG neurons and fear learning, the exact timing of PAG contributions to learning during the conditioning trial, and the contributions of different PAG columns to fear learning are poorly understood. We assessed the effects of optogenetic inhibition of lateral (LPAG) and ventrolateral (VLPAG) PAG neurons on fear learning. Using adenoassociated viral vectors expressing halorhodopsin (eNpHR3.0), we show that brief optogenetic inhibition of LPAG or VLPAG during delivery of the shock unconditioned stimulus (US) augments acquisition of contextual or cued fear conditioning and we also show that this inhibition augments post-encounter defensive responses to a non-noxious threat. Taken together, these results show that LPAG and VLPAG serve a key role in regulation of Pavlovian fear learning at the time of US delivery. These findings provide strong support for existing models which state that LPAG and VLPAG contribute to a fear prediction error signal determining variations in the effectiveness of the aversive US in supporting learning.

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Cerebellar modulation of synaptic input to freezing-related neurons in the periaqueductal gray

eLife ◽

10.7554/elife.54302 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 5

Author(s):

Christopher E Vaaga ◽

Spencer T Brown ◽

Indira M Raman

Keyword(s):

Synaptic Input ◽

Sensorimotor Integration ◽

Cell Types ◽

Cerebellar Nuclei ◽

Periaqueductal Gray ◽

D2 Receptors ◽

Defensive Behaviors ◽

Dopaminergic Modulation ◽

Freely Moving

Innate defensive behaviors, such as freezing, are adaptive for avoiding predation. Freezing-related midbrain regions project to the cerebellum, which is known to regulate rapid sensorimotor integration, raising the question of cerebellar contributions to freezing. Here, we find that neurons of the mouse medial (fastigial) cerebellar nuclei (mCbN), which fire spontaneously with wide dynamic ranges, send glutamatergic projections to the ventrolateral periaqueductal gray (vlPAG), which contains diverse cell types. In freely moving mice, optogenetically stimulating glutamatergic vlPAG neurons that express Chx10 reliably induces freezing. In vlPAG slices, mCbN terminals excite ~20% of neurons positive for Chx10 or GAD2 and ~70% of dopaminergic TH-positive neurons. Stimulating either mCbN afferents or TH neurons augments IPSCs and suppresses EPSCs in Chx10 neurons by activating postsynaptic D2 receptors. The results suggest that mCbN activity regulates dopaminergic modulation of the vlPAG, favoring inhibition of Chx10 neurons. Suppression of cerebellar output may therefore facilitate freezing.

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A neural circuit for competing approach and defense underlying prey capture

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2013411118 ◽

2021 ◽

Vol 118 (15) ◽

pp. e2013411118

Author(s):

Daniel Rossier ◽

Violetta La Franca ◽

Taddeo Salemi ◽

Silvia Natale ◽

Cornelius T. Gross

Keyword(s):

Lateral Hypothalamus ◽

Neural Circuit ◽

Prey Capture ◽

Defense Responses ◽

Periaqueductal Gray ◽

Gabaergic Neurons ◽

Defensive Responses ◽

Defensive Behaviors ◽

And Control

Predators must frequently balance competing approach and defensive behaviors elicited by a moving and potentially dangerous prey. Several brain circuits supporting predation have recently been localized. However, the mechanisms by which these circuits balance the conflict between approach and defense responses remain unknown. Laboratory mice initially show alternating approach and defense responses toward cockroaches, a natural prey, but with repeated exposure become avid hunters. Here, we used in vivo neural activity recording and cell-type specific manipulations in hunting male mice to identify neurons in the lateral hypothalamus and periaqueductal gray that encode and control predatory approach and defense behaviors. We found a subset of GABAergic neurons in lateral hypothalamus that specifically encoded hunting behaviors and whose stimulation triggered predation but not feeding. This population projects to the periaqueductal gray, and stimulation of these projections promoted predation. Neurons in periaqueductal gray encoded both approach and defensive behaviors but only initially when the mouse showed high levels of fear of the prey. Our findings allow us to propose that GABAergic neurons in lateral hypothalamus facilitate predation in part by suppressing defensive responses to prey encoded in the periaqueductal gray. Our results reveal a neural circuit mechanism for controlling the balance between conflicting approach and defensive behaviors elicited by the same stimulus.

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Brain-wide mapping of neural activity mediating collicular-dependent behaviors

10.1101/2020.08.09.242875 ◽

2020 ◽

Author(s):

Arnau Sans-Dublanc ◽

Anna Chrzanowska ◽

Katja Reinhard ◽

Dani Lemmon ◽

Gabriel Montaldo ◽

...

Keyword(s):

Neural Activity ◽

Experimental Approach ◽

Functional Organization ◽

Neuronal Cell ◽

Cell Types ◽

Electrophysiological Recordings ◽

Defensive Behaviors ◽

The Brain ◽

Overlapping Sets ◽

Insight Into

AbstractNeuronal cell-types are arranged in brain-wide circuits to guide behavior. In mice, the superior colliculus is comprised of a set of cell-types that each innervate distinct downstream targets. Here we reveal the brain-wide networks downstream of four collicular cell-types by combining functional ultrasound imaging (fUSi) with optogenetics to monitor neural activity at a resolution of ~100 μm. Each neuronal group triggered different behaviors, and activated distinct, partially overlapping sets of brain nuclei. This included regions not previously thought to mediate defensive behaviors, e.g. the posterior paralaminar nuclei of the thalamus (PPnT), that we show to play a role in suppressing habituation. Electrophysiological recordings support the fUSi findings and show that neurons in the downstream nuclei preferentially respond to innately threatening visual stimuli. This work provides insight into the functional organization of the networks governing defensive behaviors and demonstrates an experimental approach to explore the whole-brain neuronal activity downstream of targeted cell-types.

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Corrigendum to “Serotonin in the dorsal periaqueductal gray inhibits panic-like defensive behaviors in rats exposed to acute hypoxia” [Neuroscience 307 (2015) 191–198]

Neuroscience ◽

10.1016/j.neuroscience.2015.10.011 ◽

2015 ◽

Vol 310 ◽

pp. 752

Author(s):

A. Spiacci ◽

T. de Oliveira Sergio ◽

G.S.F. da Silva ◽

M.L. Glass ◽

L.C. Schenberg ◽

...

Keyword(s):

Acute Hypoxia ◽

Periaqueductal Gray ◽

Dorsal Periaqueductal Gray ◽

Defensive Behaviors

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Defensive behaviors evoked from the ventrolateral periaqueductal gray of the rat: Comparison of opioid and GABA disinhibition

Behavioural Brain Research ◽

10.1016/j.bbr.2005.05.009 ◽

2005 ◽

Vol 164 (1) ◽

pp. 61-66 ◽

Cited By ~ 25

Author(s):

Michael M. Morgan ◽

Cecilea C. Clayton

Keyword(s):

Periaqueductal Gray ◽

Defensive Behaviors

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Midbrain dopaminergic innervation of the hippocampus is sufficient to modulate formation of aversive memories

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2111069118 ◽

2021 ◽

Vol 118 (40) ◽

pp. e2111069118

Author(s):

Theodoros Tsetsenis ◽

Julia K. Badyna ◽

Julianne A. Wilson ◽

Xiaowen Zhang ◽

Elizabeth N. Krizman ◽

...

Keyword(s):

Dopaminergic Neurons ◽

Dorsal Hippocampus ◽

Memory Formation ◽

Dopamine Neurons ◽

Substantia Nigra Pars Compacta ◽

Aversive Learning ◽

Contextual Fear ◽

Dopaminergic Transmission ◽

Midbrain Dopaminergic Neurons ◽

Midbrain Dopamine

Aversive memories are important for survival, and dopaminergic signaling in the hippocampus has been implicated in aversive learning. However, the source and mode of action of hippocampal dopamine remain controversial. Here, we utilize anterograde and retrograde viral tracing methods to label midbrain dopaminergic projections to the dorsal hippocampus. We identify a population of midbrain dopaminergic neurons near the border of the substantia nigra pars compacta and the lateral ventral tegmental area that sends direct projections to the dorsal hippocampus. Using optogenetic manipulations and mutant mice to control dopamine transmission in the hippocampus, we show that midbrain dopamine potently modulates aversive memory formation during encoding of contextual fear. Moreover, we demonstrate that dopaminergic transmission in the dorsal CA1 is required for the acquisition of contextual fear memories, and that this acquisition is sustained in the absence of catecholamine release from noradrenergic terminals. Our findings identify a cluster of midbrain dopamine neurons that innervate the hippocampus and show that the midbrain dopamine neuromodulation in the dorsal hippocampus is sufficient to maintain aversive memory formation.

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Dorsal premammillary projection to periaqueductal gray controls escape vigor from innate and conditioned threats

10.1101/2021.05.02.442354 ◽

2021 ◽

Author(s):

Weisheng Wang ◽

Peter J Schuette ◽

Mimi Q La-Vu ◽

Brooke C Tobias ◽

Marta Ceko ◽

...

Keyword(s):

Periaqueductal Gray ◽

Fmri Data ◽

Central Node ◽

Defensive Behaviors ◽

Increased Activity ◽

Ensemble Activity ◽

Escape Speed

Escape from threats has paramount importance for survival. However, it is unknown if a single circuit controls escape from innate and conditioned threats. The hypothalamic dorsal premammillary nucleus (PMd) may control escape, as it is activated by escape-inducing threats and projects to the region most implicated in flight, the dorsolateral periaqueductal gray (dlPAG). We show that in mice cholecystokinin (cck)-expressing PMd cells are activated during escape, but not other defensive behaviors. PMd-cck ensemble activity can also predict future escape. Furthermore, PMd inhibition decreases escape speed from both innate and conditioned threats. Inhibition of the PMd-cck projection to the dlPAG also decreased escape speed. Lastly, human fMRI data show that a posterior hypothalamic-to-dlPAG pathway increased activity during exposure to aversive images, indicating that a similar pathway may possibly have a related role in humans. Our data identify the PMd as a central node of the escape network.

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