NPS Mediated Control of Fear Expression and Extinction: Role of Intercalated GABAergic Neurons in...

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Transcript of NPS Mediated Control of Fear Expression and Extinction: Role of Intercalated GABAergic Neurons in...

Page 1: NPS Mediated Control of Fear Expression and Extinction: Role of Intercalated GABAergic Neurons in the Amygdala Kay Jungling, Thomas Seidenbecher, Ludmila.
Page 2: NPS Mediated Control of Fear Expression and Extinction: Role of Intercalated GABAergic Neurons in the Amygdala Kay Jungling, Thomas Seidenbecher, Ludmila.

NPS Mediated Control of Fear Expression and Extinction: Role of

Intercalated GABAergic Neurons in the Amygdala

Kay Jungling, Thomas Seidenbecher, Ludmila Sosulina, Jorg Lesting, Susan Sangha,

Stewart D. Clark, Naoe Okamura, Dee M. Duangdao, Yan-Ling Xu, Rainer K.

Reinscheid, and Hans-Christian Pape

Page 3: NPS Mediated Control of Fear Expression and Extinction: Role of Intercalated GABAergic Neurons in the Amygdala Kay Jungling, Thomas Seidenbecher, Ludmila.

Intra-amygdala injections of NPS block fear-potentiated startle

• fear ↓ effect of NPS independent of locomotor activity

• Fear potentiated startle– Separate out NPS anxiolytic effect from locomotor

effect

• bi-lateral amygdala NPS injection• Fear potentiated startle protocol then motility

boxes

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Identification of a NPS Responsive Circuitry Shaping Amygdala Activity via the Endopiriform

Nucleus• https://www.youtube.com/watch?v=83PgJMd

MF0E• NPS stimulates GABAergic input of BLA

projection neurons• NPS effects in BLA interneurons• NPS stimulates glutamatergic input of BLA

interneurons• NPS stimulates glutamatergic input of BLA

projection neurons

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Fig 5: Effects of mechanical circuit dissection

(B) Cuts detaching endopiriform nucleus from BLA eliminate NPS action upon sIPSCs in BLA projection neurons

(C, D) Only dissection in between EPN and BLA diminish (C) amplitude or (D) frequency ratio: NPS/control significantly

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Endopiriform Nucleus shapes BLA activity/response

• NPS in EPN controls neural activity of BLA• NPS exerts direct action (mech) on EPN that ↑

Glu transmission• EPN required for NPS modulation of GABAA

feedback & feedforward inhibition of BLA• Conditioned fear expression– NPS to EPN ↓ contextual (where) but NOT cued

(what) fear memory in mice

Page 10: NPS Mediated Control of Fear Expression and Extinction: Role of Intercalated GABAergic Neurons in the Amygdala Kay Jungling, Thomas Seidenbecher, Ludmila.

Jungling Intro

• Injection of NPS into BLA – anxiolytic effect– acute reduction in general anxiety and – accelerated extinction of conditioned fear– injection of the NPS receptor antagonist SHA 68

exerted functionally opposing effects.• NPS ↑ glutamatergic synaptic transmission to

intercalated GABAergic neurons of medial paracapsular cluster via a presynaptic effect– involving principal neurons in the LA

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medial paracapsular cluster

Source: http://dx.doi.org.ezproxy.usd.edu/10.1016/j.brainres.2012.03.047

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Intro Cont.

• NPSR’s densely expressed in the mouse BLA– at single-cell level, in LA principal neurons – Not in paracapsular GABAergic neurons

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Methods

• C57BL/6J mice, 8-12 wks old• Bilateral injections into BLA/LA• One animal per behavioral test/drug group• Open field, EPM, dark-light test, fear cond.• Amygdala coronal slices, whole-cell patch

clamp

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Figure 1                           Effects of NPS in the LA/BLA on generalized anxiety behavior in the open field and elevated plus maze

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Fig 3: Target specific effect of NPS on evoked EPSCsmpara neurons provide a feedforward inhibitory gate for signals between BLA and CeA

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Fig 4: Lack of NPS modulatory influence in LA Principle Neurons (PN) and LA local GABAergic interneurons (IN)

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Fig 6: Presynaptic site of NPS modulation

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Fig 7: NPS receptor expression in the amygdala

opt: optic tractBLA: basolateral amygdaloid complex, anterior partBMA: basomedial amygdaloid nucleus, anterior part MeAV: medial amygdaloid nucleus, anteroventral part ACo: anterior cortical amygdaloid nucleusic: internal capsuleDI: dysgranular insular cortexGI: granular insular cortex AIP: agranular insular cortex, posterior partLaDL: lateral amygdaloid nucleus, dorsolateral partDEn: dorsal endopiriform nucleus

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Fig 8: NPS enforces feed forward inhibition on principal neurons in the central nucleus of the amygdala (CeA)

Page 22: NPS Mediated Control of Fear Expression and Extinction: Role of Intercalated GABAergic Neurons in the Amygdala Kay Jungling, Thomas Seidenbecher, Ludmila.

Take Home

• Endogenous NPS has a dual function to acutely attenuate anxiety-like responses and later facilitate extinction of aversive memories

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Thank you